The threshold value is similar in men and women in that for a given waist circumference, men and women had comparable levels of abdominal visceral adipose tissue. Thus, waist circumference, a convenient and simple measurement unrelated to height 46 and correlated with BMI and WHR 47 , determines the extension of abdominal obesity, which appears closely linked to abdominal visceral adipose tissue deposition.

Furthermore, while changes in waist girth reflect changes in risk factors for cardiovascular disease 48 and other forms of chronic disease, the risks vary in different populations; therefore, globally applicable cut-off points cannot be developed.

For example, abdominal fatness has been shown to be less strongly associated with risk factors for cardiovascular disease and type 2 diabetes in black women than in white women Risk factors such as total and HDL cholesterol were correlated with subcutaneous and abdominal fat areas by CT as well as their sum in healthy nonobese Asian Indians.

On the other hand, while there was an association of visceral adiposity with insulin secretion during an oral glucose test in men, such was not found in women In addition, it has been reported that visceral obesity is strongly related to coronary heart disease risk factors in nonobese Japanese-American men Also, people of South Asian Indian, Pakistani, and Bangladeshi descent living in urban societies have a higher incidence of obesity complications than other ethnic groups These complications are seen to be associated with abdominal fat distribution, which is markedly higher for a given level of BMI than in Europeans.

Finally, although women have an almost equivalent absolute risk of coronary heart disease CHD to men at the same WHR 53 , 54 , they show increases in relative risk of CHD at lower waist circumferences than men.

Thus, there is a need to develop sex-specific waist circumference cut-off points appropriate for different populations. The studies by Ferland et al.

Therefore, the waist circumference, and the abdominal sagittal diameter as will be discussed below , are the anthropometric indexes preferred over the WHR to estimate the amount of abdominal visceral fat and related cardiovascular risk profile.

Using the equations for prediction, multiscan CT was used to determined visceral adipose tissue volume from the waist circumference in a sample of 17 males and 10 females with different degrees of obesity Again, it was concluded that the WHR is a suboptimal predictor of visceral adipose tissue volume.

Abdominal sagittal diameter. The sagittal diameter is measured with a ruler as the vertical distance from the horizontal spirit level to the examination table after a normal expiration Kvist et al.

The correlation of the sagittal diameter with visceral fat volume was 0. The correlations between the waist circumference and visceral fat were, respectively, 0. These correlations are considerably higher than those observed between anthropometric variables and the visceral fat area measured at the level of the umbilicus in obese men and women Ferland et al.

Desprès et al. Busetto et al. It is very likely, therefore, that the range of fatness in subjects studied greatly influences the magnitude of the correlations and perhaps also the comparison between the sagittal diameter and the waist circumference with regard to their utility in predicting intraabdominal fat.

In addition, the distinction between studies that used only visceral fat area and those that calculated visceral fat volume from multiple scans may be important to make Ross et al. A study from the Canadian group 38 conducted in a large group of males and females evaluated systematically the three anthropometric indexes and their association with abdominal visceral adipose and subcutaneous areas measured by CT between the fourth and fifth lumbar vertebrae and metabolic profile.

As seen in Table 1 , there was a strong association between waist girth and body fat mass, the slope of the regression line being steeper in women data not shown. With relation to the abdominal visceral fat area, for a given waist circumference, men and women had similar levels and the slopes of the regression lines were not different between genders.

Essentially similar results were observed with the abdominal sagittal diameter. However, in contrast with waist circumference, the slopes of regression of abdominal sagittal diameter to abdominal visceral fat area were significantly different between genders and were steeper in men data not shown.

Finally, it can be seen that the WHR was less strongly correlated with total body fat mass and abdominal visceral and subcutaneous areas than the other indexes. This study demonstrated that most of the variance in waist girth and abdominal sagittal diameter can be explained by variations in body fat mass and in abdominal visceral and subcutaneous adipose tissue areas 0.

With relation to the metabolic variables related to cardiovascular risk plasma triglycerides and high-density lipoprotein cholesterol levels, fasting and postglucose glucose and insulin levels , in women, the waist circumference and the abdominal sagittal diameter were more closely related to the metabolic variables than the WHR, whereas such differences were not apparent in men.

They concluded that waist circumference values above approximately cm, abdominal sagittal diameter values greater than 25 cm, and WHR values greater than 0. Correlations r values between the anthropometric indexes and body fat mass, abdominal visceral, and abdominal subcutaneous fat areas in 81 men and 70 women.

Correlations between sagittal diameter and waist circumference are usually quite high [ e. Although the sagittal supine diameter can be studied with relatively good precision 61 , it is clear that this measurement requires appropriate equipment and skilled personnel.

Since most people are measuring the WHR as an indicator of visceral fat, the focus should be switched to the waist girth alone without affecting the ranking of individuals with respect to visceral fat when based on the waist circumference compared with the sagittal diameter Computed tomography CT.

CT can be considered the gold standard not only for adipose tissue evaluation but also for multicompartment body measurement 61 , The reported error for the determination of total adipose tissue volume after performing 28 scans is 0.

The subcompartments of adipose tissue volume, visceral and subcutaneous adipose tissue, can be accurately measured with errors of 1. In eight nonobese Swedish males evaluated by the multiscan CT technique, the volume of visceral abdominal adipose tissue in the intraperitoneal and retroperitoneal compartments was found to be 1.

Using a multislice magnetic resonance protocol, Abate et al. In effect, in 13 lean males, Abate et al. If only one scan is used to measure the visceral adipose tissue area, a strictly defined longitudinal level is very important since the average visceral adipose tissue area shifts if there is a change in position, even of a few centimeters.

This, according to Sjöström et al. Instead, the longitudinal level must be defined in a strict relation to the skeleton, usually between the L4 and L5 vertebrae. The subjects are examined in a supine position with their arms stretched above their heads. The choice to perform the scan at the level of the umbilicus was initially proposed by Borkan et al.

Subsequently, Tokunaga et al. In addition to the recommendations of the Japanese investigators, studies from Korea 20 and from our clinic use the scan at the umbilicus. Visceral fat is defined as intraabdominal fat bound by parietal peritoneum or transversalis fascia, excluding the vertebral column and the paraspinal muscles; subcutaneous fat is fat superficial to the abdominal and back muscles.

Subcutaneous fat area is calculated by subtracting the intraabdominal fat area from the total fat area. In addition, visceral fat increases with age Figure 1 shows cross-sectional abdominal areas obtained by CT at the level of the umbilicus in two women matched for the same BMI, who differed markedly in the accumulation of fat in the abdominal cavity but less so in the subcutaneous abdominal fat.

Computed tomography showing cross-sectional abdominal areas at umbilicus level in two patients demonstrating variation in fat distribution.

A, Visceral type yr-old female, B, Subcutaneous type yr-old female, In obese subjects the level of the umbilicus can change from one patient to another, thus changing the visceral adipose tissue area; therefore, it is advisable that the scan area be defined in strict relation to the skeleton.

Chowdhury et al. However, the values for abdominal cut-off points were related to increased cardiovascular risk Table 2. Using the scan at the umbilicus as described by several investigators gave results similar to, although somewhat lower than, those reported using the L4-L5 level.

Abdominal visceral adipose tissue area cut-off points related to increased cardiovascular risk. Regarding the relationship between the modifications in subcutaneous and visceral adipose tissue, with changes in body weight, it was shown that after severe weight loss, subcutaneous fat at the abdominal level is lost in greater proportion than visceral fat, but the mechanism of these differential changes in both compartments of abdominal fat is unknown, suggesting that visceral fat does not reflect nutritional status to the extent that sc fat does In the same way, published data suggest that, at least in relative terms, visceral fat increases less than subcutaneous fat with increased body weight However, because the amount of subcutaneous abdominal fat is calculated indirectly, it is likely that significant measurement error could be introduced Regarding the reproducibility of CT measurement of visceral adipose tissue area, Thaete et al.

The duplication occurred after the initial scan; the subjects were repositioned before repeat scanning. As indicated in the Introduction , individuals with a high accumulation of visceral abdominal fat, as shown by CT scans, had an increased risk for development of type 2 diabetes, dyslipidemia, and coronary heart disease.

Table 2 shows the thresholds above which metabolic complications would be more likely to be observed in visceral adipose tissue areas. Desprès and Lamarche 73 , Hunter et al. They found that a value above cm 2 was associated with an increased risk of coronary heart disease in pre and postmenopausal women 75 ; the same group 74 found that males with abdominal visceral fat cross-section areas measuring more than cm 2 were clearly at an increased risk for coronary disease.

On the other hand, Desprès and Lamarche 73 found that in both men and women a value of cm 2 was associated with significant alterations in cardiovascular disease risk profile and that a further deterioration of the metabolic profile was observed when values greater than cm 2 of visceral adipose tissue were reached.

From the same center, Lemieux et al. It was concluded that waist circumference was a more convenient anthropometric correlate to visceral adipose tissue because its threshold values did not appear to be influenced by sex or by the degree of obesity.

Anderson et al. The most extensive studies using a single CT scan at umbilical level was done by Matsuzawa and colleagues 17 , However, they did not present the raw data on visceral and subcutaneous areas but only their ratios, thus precluding their inclusion in Table 2.

In another study, performed in Japan by Saito et al. Lottenberg et al. Magnetic resonance imaging MRI. MRI provided results similar to CT without exposure to ionizing radiation, the main problem with CT multislice measurements. It demonstrated good reproducibility for total and visceral adipose tissue volumes 63 , which were slightly lower than previously reported using CT 55 , although the percent contribution of visceral to total adipose tissue volume was similar 18 vs.

Subcutaneous adipose tissue and visceral fat areas at the L4-L5 level determined in 27 healthy men by MRI were These areas were highly predictive of the corresponding volume measurements computed from the scan MRI, confirming the CT studies of Kvist et al.

Two studies have compared estimates of subcutaneous and visceral adipose tissue by CT and MRI. Comparison between MRI and CT in seven subjects showed a high degree of agreement in measurement of total subcutaneous adipose tissue area but not visceral adipose tissue area As already mentioned, MRI has been validated in three cadavers, confirming its accuracy Ultrasound US.

US subcutaneous and intraabdominal thicknesses, the latter corresponding to the distance between abdominal muscle and aorta, were measured 5 cm from the umbilicus on the xipho-umbilical line with a 7. The intraindividual reproducibility of US measurements was very high both for intraabdominal and subcutaneous thickness as well as for interoperators 83 , Several studies demonstrated a highly significant correlation between the intraabdominal adipose tissue determined by CT and by US.

A decade ago, Armellini et al. In a more recent study, Tornaghi et al. In a study of men C. Leite, D. Matsuda, B. Wajchenberg, G. Cerri, and A. Halpern, unpublished data , in which In obese women, after a 6-kg weight loss, a significant decrease was found in intraabdominal fat but not in subcutaneous adipose tissue, as determined by both CT and US There was also a significant correlation between changes in intraabdominal adipose tissue using both techniques, indicating that US can be used in the evaluation of body fat distribution modifications during weight loss.

This is another confirmation of the reliability of the US intraabdominal determinations. The amount of visceral fat increases with age in both genders, and this increase is present in normal weight BMI, In a study of subjects 62 males and 68 females with a wide range of age and weight , Enzi et al.

This fat topography was retained in young and middle-aged females up to about 60 yr of age, at which point there was a change to an android type of fat distribution.

This age-related redistribution of fat is due to an absolute as well as relative increment in visceral fat depots, particularly in obese women, which could be related to an increase in androgenic activity in postmenopausal subjects. On the other hand, they showed that males at any age tend to accumulate fat at the visceral depot, increasing with age and BMI increase.

In the male, a close linear correlation between age and visceral fat volume was shown, suggesting that visceral fat increased continuously with age Although this correlation was also present in women, the slope was very gentle in the premenopausal condition.

It became steeper in postmenopausal subjects, almost the same as in males Further, Enzi et al. From the published data 68 , 90 , it can be concluded that both subcutaneous and visceral abdominal fat increase with increasing weight in both sexes but while abdominal subcutaneous adipose tissue decreases after the age of 50 yr in obese men, it increases in women up to the age of 60—70 yr, at which point it starts to decline Fowler et al.

Finally, as previously indicated, visceral fat is more sensitive to weight reduction than subcutaneous adipose tissue because omental and mesenteric adipocytes, the major components of visceral abdominal fat, have been shown to be more metabolically active and sensitive to lipolysis Lemieux et al.

In addition, the adjustment for differences in visceral fat between men and women eliminated most of the sex differences in cardiovascular risk factors.

There is evidence supporting the notion that abdominal visceral fat accumulation is an important correlate of the features of the insulin-resistant syndrome 23 , 24 , 29 but this should not be interpreted as supporting the notion of a cause and effect relationship between these variables This subject will be discussed later on.

The correlations of abdominal visceral fat mass evaluated by CT or MRI scans with total body fat range from 0. They tend to be lower in the lean and normal weight subjects than in the obese As indicated by Bouchard et al.

When they examined the relationship of total body fat mass to visceral adipose tissue accumulation in men and in premenopausal women, Lemieux et al. Furthermore, the relationship of visceral adipose tissue to metabolic complications was found to be independent of concomitant variation in total body fat, and it was concluded that the assessment of cardiovascular risk in obese patients solely from the measurement of body weight or of total body fatness may be completely misleading 19 , 22 , 36 , Indeed, it appears that only the subgroup of obese individuals characterized by a high accumulation of visceral adipose fat show the complications predictive of type 2 diabetes and cardiovascular disease On the other hand, after adjustment for total body fat, Abate et al.

Intraabdominal visceral fat is associated with an increase in energy intake but this is not an absolute requirement. Positive energy balance is a strong determinant of truncal-abdominal fat as shown by Bouchard and colleagues 96 in overfeeding experiments in identical twins.

The correlations between gains in body weight or total fat mass with those in subcutaneous fat on the trunk reached about 0. In contrast, these correlations attained only 0. Thus, positive energy balance does not appear to be a strong determinant of abdominal visceral fat as is the case with other body fat phenotypes 7.

In effect, as discussed in the CT section of imaging techniques for evaluation of intraabdominal visceral fat, some investigators 70 , 71 have shown that either when the subjects lose or increase their weight, particularly females, visceral fat is lost or gained, respectively, less than subcutaneous fat at the abdominal level.

However, at variance from these data, Zamboni et al. Similarly, as already mentioned, Smith and Zachwieja 32 noted that all forms of weight loss affect visceral fat more than subcutaneous fat percentage wise , and there was a gender difference, with men appearing to lose more visceral fat than women for any given weight loss.

LPL activity, being related to the liberation of the lipolytic products [from chylomicra and very-low-density lipoproteins VLDL ] to the adipocytes for deposit as triglycerides, is a key regulator of fat accumulation in various adipose areas, since human adipose tissue derives most of its lipid for storage from circulating triglycerides.

However, adipocytes can synthesize lipid de novo if the need arises, as in patients with LPL deficiency According to Sniderman et al. The increase of visceral fat masses with increasing total body fat was explained by an increase of fat cell size only up to a certain adipocyte weight.

However, with further enlargement of intraabdominal fat masses with severe obesity, the number of adipocytes seems to be elevated , In women, but not in men, omental adipose tissue has smaller adipocytes and lower LPL activity than subcutaneous fat depots since variations in LPL activity parallel differences in fat cell size 7.

When adipocytes enlarge in relation to a gain in body weight, the activity of LPL increases in parallel, possibly as a consequence of obesity-related hyperinsulinism.

The higher basal activity of adipose tissue LPL in obesity is accompanied by a lower increment after acute hyperinsulinemia Lipid accumulation is favored in the femoral region of premenopausal women in comparison with men In the latter, LPL activity as well as the LPL mRNA levels were greater in the abdominal than in gluteal fat cells, while the opposite was observed in women, suggesting that regional variation of gene expression and posttranslational modification of LPL could potentially account for the differences between genders in fat distribution With progressive obesity, adipose tissue LPL is increased in the depots of fat in parallel with serum insulin.

However, when obese subjects lost weight and became less hyperinsulinemic, adipose LPL increased further and the patients who were most obese showed the largest increase in LPL, suggesting that very obese patients are most likely to have abnormal LPL regulation, independent of the influence of insulin.

In response to feeding, the increase in LPL is, as indicated, due to posttranslational changes in the LPL enzyme. However, the increased LPL after weight loss involved an increase in LPL mRNA levels, followed by parallel increases in LPL protein and activity Because the response to weight loss occurred via a different cellular mechanism, it is probably controlled by factors different from the day-to-day regulatory forces.

In addition, because the very obese patients demonstrated a larger increase in LPL with weight loss than the less obese patients, these data suggest a genetic regulation of LPL that is most operative in the very obese The role of sex steroids, glucocorticoids, and catecholamines in the regulation of adipose tissue LPL activity in various fat depots will be discussed in the section on hormonal regulation of abdominal visceral fat.

Lipid mobilization and the release of FFA and glycerol are modulated by the sympathetic nervous system. Catecholamines are the most potent regulators of lipolysis in human adipocytes through stimulatory β l - and β 2 -adrenoreceptors or inhibitoryα 2-adrenoreceptors A gene that codes for a third stimulatory β -adrenoreceptor, β 3 -adrenoreceptor, is functionally active principally in omental adipocytes but also present in mammary fat and subcutaneous fat in vivo In both genders and independently of the degree of obesity, femoral and gluteal fat cells exhibit a lower lipolytic response to catecholamines than subcutaneous abdominal adipocytes, the latter showing both increased β l - and β 2 -adrenoreceptor density and sensitivity and reduced α2-adrenoreceptor affinity and number Refs.

The increased sensitivity to catecholamine-induced lipolysis in omental fat in nonobese individuals is paralleled by an increase in the amount of β l - and β 2 -receptors, with normal receptor affinity and normal lipolytic action of agonists acting at postadrenoreceptor steps in the lipolytic cascade , ; this is associated with enhanced β 3 -adrenoreceptor sensitivity, which usually reflect changes in receptor number in comparison with subcutaneous adipocytes , Comparison of lipolysis, antilipolysis, and lipogenesis in omental and subcutaneous fat in nonobese and obese individuals.

Adipocytes from obese subjects generally show increased lipolytic responses to catecholamines, irrespective of the region from which they are obtained, and enhanced lipolysis in abdominal compared with gluteo-femoral fat 21 , The antilipolytic effect is also reduced in vitro in obesity, both in omental and subcutaneous adipocytes The typical features of visceral fat, e.

An increased β 3 -adrenoreceptor sensitivity to catecholamine stimulation may lead to an increased delivery of FFA into the portal venous system, with several possible effects on liver metabolism.

These include glucose production, VLDL secretion, and interference with hepatic clearance of insulin , resulting in dyslipoproteinemia, glucose intolerance, and hyperisulinemia. Lönnqvist et al.

They observed that males had a higher fat cell volume with no sex differences in the lipolytic sensitivity to β l - and β 2 -adrenoreceptor-specific agonists or in the antilipolytic effect of insulin.

However, the lipolytic β 3 -adrenoreceptor sensitivity was 12 times higher in men, and the antilipolytic α2-adrenoreceptor sensitivity was 17 times lower in men.

It was concluded that in obesity, the catecholamine-induced rate of FFA mobilization from visceral fat to the portal venous system is higher in men than women.

This phenomenon is partly due to a larger fat cell volume, a decrease in the function ofα 2-adrenoceptors, and an increase in the function of β 3 -adrenoreceptors. These factors may contribute to gender-specific differences observed in the metabolic disturbances accompanied by obesity, i.

Glucocorticoid receptors. Glucocorticoid receptors, one of the most important receptors for human adipose tissue function, are involved in metabolic regulation and distribution of body fat under normal as well as pathophysiological conditions. Glucocorticoid receptors in adipose tissue show a regional variation in density with elevated concentrations in visceral adipose tissue In spite of the lower receptor density, the elevated cortisol secretion results in clearly increased net effects of cortisol.

Androgen and estrogen receptors. Adipocytes have specific receptors for androgens, with a higher density in visceral fat cells than in adipocytes isolated from subcutaneous fat.

Unlike most hormones, testosterone induces an increase in the number of androgen receptors after exposure to fat cells , thereby affecting lipid mobilization. This is more apparent in visceral fat omental, mesenteric, and retroperitoneal because of higher density of adipocytes and androgen receptors, in addition to other factors However, at variance with the effects of testosterone, dihydrotestosterone treatment does not influence lipid mobilization In females, there is an association between visceral fat accumulation and hyperandrogenicity, despite the documented effects of testosterone on lipid mobilization and the expected decrease in visceral fat depots.

The observation that visceral fat accumulation occurs only in female-to-male transsexuals after oophorectomy suggests that the remaining estrogen production before oophorectomy was protective The androgen receptor in female adipose tissue seems to have the same characteristics as that found in male adipose tissue.

However, estrogen treatment down-regulates the density of this receptor, which might be a mechanism whereby estrogen protects adipose tissue from androgen effects. Estrogen by itself seems to protect postmenopausal women receiving replacement therapy from visceral fat accumulation Estrogen receptors are expressed in human adipose tissue and show a regional variation of density, but whether the quantity of these receptors is of physiological importance has not been clearly established With regard to progesterone, adipose cells seem to lack binding sites and mRNA for progesterone receptors, indicating that progesterone acts through glucocorticoid receptors GH receptors.

While it is well established that GH has specific and receptor-mediated effects in adipose tissue of experimental animals, the importance of GH receptors in human adipose tissue is not fully elucidated at present although the available data indicate a functional role. However, GH is clearly involved in the regulation of visceral fat mass in humans.

Acromegaly, a state of GH excess, is associated with decreased visceral fat while in GH deficiency there is an increase in visceral fat and in adults with GH deficiency, recombinant human GH replacement therapy results in adipose tissue redistribution from visceral to subcutaneous locations; however, the regulation of adipose tissue metabolism requires synergism with steroid hormones A direct demonstration of a regulation of the GH receptor in human fat cells has not yet been performed Thyroid hormone receptors.

Thyroid hormones have multiple catabolic effects on fat cells as a result of interactions with the adrenergic receptor signal transduction system, and most of these interactions are also present in human fat cells There are data regarding the characterization of the nuclear T 3 receptor in human fat cells Although receptor regulation has not yet been demonstrated, there is little doubt that the thyroid hormone receptors are important for the function of human adipose tissue Further, no data are available on the correlation between visceral fat mass and thyroid hormone levels.

Adenosine receptors. Adenosine behaves as a potent antilipolytic and vasodilator agent and can be considered as an autocrine regulator of both lipolysis and insulin sensitivity in human adipose tissue.

Site differences in ambient adenosine concentration, perhaps controlled by blood flow, may also modulate adipose tissue metabolism 7. Adenosine content is higher in omental than in abdominal subcutaneous adipose tissue, but the receptor-dependent inhibition of lipolysis is, as indicated before , less pronounced in the former than in the latter depot Thereafter, sc adipose tissue 1—2 g was obtained from the paraumbilical region by needle aspiration under local anesthesia using 5—10 ml 0.

It has previously been demonstrated that this procedure does not influence adipocyte metabolism The tissue samples were immediately transported to the laboratory. None of the obese subjects reported important weight changes during the 4 wk proceeding each fat biopsy.

Isolated fat cells were prepared and isolated according to Rodbell In brief, adipocytes were separated from stromal cells by treatment in a shaking bath at 37 C for 60 min with 0. Adipocyte suspensions were then rinsed three times in collagenase-free buffer using nylon filters. Fat cell sizes were measured by direct microscopy, and the mean adipocyte diameter was calculated from measurements of cells.

The total lipid weight of the incubated fat cells was determined after organic extraction. The number of fat cells incubated was determined by dividing total lipid weight by fat cell weight. The lipolysis assay has previously been described in detail The latter included noradrenaline, which is a natural nonselective α- and β-agonist; isoprenaline, a nonselective β-adrenoceptor agonist; forskolin, which stimulates adenylyl cyclase; and Bu 2 cAMP, which is a phosphodiesterase-resistant cAMP analog that stimulates the PKA-HSL complex.

After the incubation, an aliquot of the medium was removed, and glycerol, which was used as a measurement of the lipolysis rate, was analyzed using a bioluminescence method All agents caused a concentration-dependent stimulation of lipolysis that reached a plateau at the highest concentrations of agonist in each individual experiment.

The formula used to calculate cell surface area has been discussed in detail previously 10 , We calculated the rate of glycerol release at maximum effective concentration for each of the lipolytic agents used lipolytic capacity.

The amount of HSL protein in adipose tissue was determined as described previously The homogenate was centrifuged at 14, rpm for 30 min, and the infranatant was removed and saved. All steps were performed at 4 C to minimize the risk of protein degradation.

The protein content in each sample was determined using a kit of reagents from Pierce Chemical Co. Rockford, IL. One hundred micrograms of total protein were then loaded on polyacrylamide gels and separated by standard SDS-PAGE. To control for differences in gel migration, exposure time, antibody incubation, etc.

Blots were blocked for 1 h in room temperature in Tris-buffered saline with 0. This was followed by an overnight incubation at 4 C in the presence of antibodies directed against HSL. HSL antibodies were generated by one of the authors C. Secondary antibodies conjugated to horseradish peroxidase were obtained from Sigma St.

Louis, MO; α-rabbit, ; α-chicken, Antigen-antibody complexes were detected by chemiluminescence using a kit of reagents from Pierce Chemical Co. Supersignal , and blots were exposed to high performance chemiluminescence film Amersham Pharmacia Biotech.

BSA fraction V, lot 63F , Clostridium histolyticum collagenase type I, forskolin, Bu 2 cAMP, and glycerol kinase from Escherichia coli G were obtained from Sigma. Isoprenaline was obtained from Hässle Molndal, Sweden.

ATP monitoring reagent containing firefly luciferase was purchased from LKBWallac, Inc. Turku, Finland. All other chemicals were of the highest grade of purity commercially available.

Data are presented as the mean ± sem and were compared using paired or unpaired t test and ANOVA. Calculations were made using the StatView software program Abacus Concepts, Berkeley, CA.

The characteristics of the study groups are presented in Table 1. At baseline obese men and women showed classical abnormalities. All of these parameters improved markedly 2 yr after bariatric surgery.

The range of BMI loss after surgery was 3. Figure 1 shows for illustrative purposes the mean concentration-response curves for noradrenaline lipolysis per cell in men and women before and 2 yr after weight loss compared with lean controls. In all experiments noradrenaline increased lipolysis in a concentration-dependent fashion.

In women the mean baseline curve of the obese subjects was elevated compared to that in lean subjects and was also normalized after weight loss. However, in men the three mean curves did not differ much in their positions in the graph. Rate of noradrenaline-stimulated lipolysis.

The individual concentration-response curves for the different lipolytic agents were analyzed for maximum effects. The group data for lipolysis per cell are given in Table 2. Maximum stimulated lipolysis of sc adipose tissue in obese men and women before and 2 yr after bariatric surgery compared to lean controls.

A, Lean controls; B, obese patients before weight loss; C, obese patients after weight loss. At 2 yr after weight reduction, basal lipolysis and maximally stimulated lipolysis in the obese female group had decreased to rates equal to those in the nonobese females.

In obese men, the basal rate of lipolysis was 2-fold elevated at baseline and was not influenced by weight reduction at the 2 yr follow-up. Maximum lipolysis induced by noradrenaline, isoprenaline, forskolin, and Bu 2 cAMP was not altered in obese men at baseline and did not change after a 2-yr weight reduction.

Group data for lipolysis were also expressed per cell surface area Table 3. Obese men showed no difference from lean men in lipolysis either before or after weight reduction, although stimulated lipolysis actually improved at a borderline significant level after the decrease in body weight.

In obese women basal lipolysis was increased at baseline and was completely normalized after weight reduction. Stimulated lipolysis was similar in obese and nonobese women, although it decreased at a borderline level of significance after surgery.

To determine whether adipocyte lipolysis was stable after weight reduction, six obese women and four obese men were followed at regular intervals until 3 yr after bariatric surgery, and adipose tissue biopsies were obtained at 0, 2, and 3 yr. Data for basal lipolysis, Bu 2 cAMP-stimulated lipolysis, and BMI are shown in Fig.

BMI decreased gradually in men and women, with the major part of the decrease occurring from 0—2 yr. In women the rate of basal and Bu 2 cAMP-induced lipolysis decreased markedly from 0—2 yr and was thereafter almost constant.

However, in men the lipolytic rates were constant from 0—3 yr. Similar results were obtained with isoprenaline and forskolin values not shown. Top , BMI of obese men and women before and 2 and 3 yr after bariatric surgery. A comparison of lipolysis between men and women before weight loss revealed that both basal and stimulated lipolysis values per cell were significantly higher in obese women P values ranging from 0.

There was no significant difference in stimulated lipolysis between genders after weight loss P values ranging from 0. There were no important gender differences in lipolysis in nonobese subjects. The relationship between fat cell size and lipolytic capacity was examined using simple regression analysis for obese and lean patients Fig.

There were significant correlations between fat cell size and basal lipolysis both in men and women Fig. In Fig. However, these outliers responded to weight loss in the same way as the other men, and when they were omitted in statistical analysis, the results were the same as when they were included.

However, a gender difference was observed when studying maximally stimulated lipolysis. The maximum sc lipolysis induced by Bu 2 cAMP, forskolin, or isoprenaline showed a strong correlation to fat cell size in women, but there was no correlation in men. Similar results were obtained with isoprenaline and forskolin graphs not shown.

In women, the reduced basal and stimulated lipolysis values after weight reduction were distributed evenly along the same regression line as the baseline values.

Linear relationship between basal lipolysis no agent present and sc fat cell volume in obese women A , men B , and their lean controls before and after weight loss. Linear relationship between Bu 2 cAMP-stimulated lipolysis and sc fat cell volume in obese women C and lack of correlation between Bu 2 cAMP-stimulated lipolysis and fat cell volume in obese men D.

To evaluate the expression of proteins involved in lipolytic activity after weight reduction, we obtained sc adipose tissue samples from a limited set of subjects 7 men and 10 women before and after weight reduction.

The samples were run on the same Western blot 1 for men and 1 for women. To evaluate absolute amounts of detected protein we also compared sc adipose tissue from lean control subjects 8 men and 8 women with the obese samples obtained before weight reduction.

The control subjects were chosen at random. Obese and lean men were run on one Western blot, and female samples on another. Total cytosolic protein was isolated and separated by Western blotting.

Immunodetection was performed with antibodies directed against HSL. In the present study marked differences in the influence of obesity and subsequent body weight reduction on lipolysis regulation were seen between women and men.

In obese women the basal rate of lipolysis as well as the lipolytic capacity measured by agents acting at various levels of the lipolytic cascade were markedly increased when expressed per fat cell. However, lipolytic capacity per cell surface area was similar in obese and nonobese women.

It is well known that the lipolytic rate in fat cells is related to fat cell size. It is very likely that the influence of obesity and weight reduction in women above all is related to changes in fat cell size, which is increased in obesity and normalized after weight reduction.

Firstly, in the whole group of women there was a strong relationship between lipolysis rate per cell and fat cell size. Secondly the rates of lipolysis per cell in adipocytes of weight-reduced obese women were distributed along the same regression line as baseline values.

In obese men the basal rate of lipolysis per cell was increased, but, in contrast to women, it was not influenced by weight reduction despite the fact that fat cell size decreased after bariatric surgery to the same extent in men as in women. The lipolytic capacity and the effect of noradrenaline on lipolysis were not influenced by either obesity or weight reduction when expressed per cell.

Furthermore, there was no relationship between lipolytic capacity per cell and fat cell size in men. Lipolysis per cell surface area was not influenced by obesity in men, although it tended to improve after weight reduction.

These data strongly indicate that obesity influences lipolysis in the sc abdominal site in a different manner in men and women. The increased rate per cell, but not per cell surface area, observed in women indicates that obesity-mediated changes in women probably are due to the change in fat cell size.

In men the increase in the basal rate of lipolysis might be a primary defect or at least more resistant to weight reduction. It is possible that the gender difference in lipolytic capacity could be due to the fact that women adapt their lipolysis to obesity. The increase in lipolytic capacity in obese women could be a protective phenomenon.

Men do not seem to be able to increase their lipolytic capacity in sc abdominal adipose tissue when becoming obese. This might at least in part explain why men are more prone to accumulate fat in the abdominal region than are women.

The observation that lipolysis per cell differed between obese men and women, but not between lean subjects of either sex, further suggests that obesity influences lipolysis differently in males and females. A lower maximal lipolytic capacity in sc abdominal adipocytes in obese vs.

lean subjects has previously been reported The previous study 10 , in contrast to the present, was conducted on a mixed population of both men and women.

Furthermore, the controls in the present study [as opposed to the previous one 10 ] had no family history of obesity. It has been shown that family history of obesity influences lipolysis in lean subjects Data from basal lipolysis were somewhat different from those from stimulated lipolysis.

It should be noted that the meaning of basal lipolysis measured in vitro is unclear, as fat cells in vivo always are exposed to regulatory hormones. However, the fact that basal lipolysis in obese women was elevated when expressed per cell and per cell surface area may suggest that it is not influenced by fat cell size.

It should be stressed that our findings may only relate to sc abdominal fat. Cell , 20—44 FoxO1 interacts with transcription factor EB and differentially regulates mitochondrial uncoupling proteins via autophagy in adipocytes. Cell Death Discov.

Tamoxifen reduces fat mass by boosting reactive oxygen species. Cell Death Dis. Targeting FoxO1 with AS suppresses adipogenesis. Cell Cycle 13 , — Komatsu, M. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.

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Cheng, Z. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Download references. Funding for this work was provided, in part, by USDA National Institute of Food and Agriculture Hatch Project Z.

Department of Human Nutrition, Foods, and Exercise, Fralin Life Science Institute, College of Agriculture and Life Science, Virginia Tech, Blacksburg, VA, , USA. Zhipeng Tao, Louise D. Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

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Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Estradiol signaling mediates gender difference in visceral adiposity via autophagy. Cell Death Dis 9 , Download citation. Received : 09 October Revised : 30 January Accepted : 01 February Published : 22 February Anyone you share the following link with will be able to read this content:.

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International Urology and Nephrology Skip to main content Thank you for visiting nature. Download PDF. Abstract Excessive adiposity particularly visceral fat mass increases the risks of developing metabolic syndrome. Introduction White adipose or fat tissues WAT play a central role in metabolic homeostasis through energy storage and endocrine functions 1 , 2.

Results Female mice had lower visceral WAT vWAT mass than male mice A higher vWAT volume in men than women has been observed across races 14 , Full size image. Discussion Increased visceral adiposity has been strongly associated with higher risks of developing metabolic disorders 9 , 10 , 11 , 12 , Oil Red O staining The Oil Red O working solution was freshly prepared by mixing 0.

Autophagy flux assay To measure autophagy flux in cultured cells, we treated 3T3L1 preadipocytes, stromal vascular cells, and mature adipocytes day 10 with bafilomycin A1 inhibitor of autophagosome acidification, at 0. References Kershaw, E.

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However, the association with abdominal visceral fat area was seen only in subjects of the lower tertile of the percent body fat level. The consistent association between the glucocorticoid receptor polymorphism detected with Bcl I and abdominal visceral fat area suggested that this gene or a locus in linkage disequilibrium with the Bcl I restriction site may contribute to the accumulation of abdominal visceral adipose tissue With respect to the linkage studies, only a few studies of body fat or fat distribution with random genetic markers or candidate genes have been reported using the sibling-pair linkage method.

One of the few reported studies relative to the visceral fat mass was the evaluation of a sib-pair linkage analysis from the QFS between five microsatellite markers encompassing about 20 cM in the Mob-1 region of the human chromosome 16pp These results suggested to the authors that this region of the human genome contains a locus affecting the amount of visceral fat and lipid metabolism as also shown by the association studies indicated above.

The other population and intrafamily association study used a polymorphic marker LIPE in the hormone-sensitive lipase gene, located on chromosome 19q In conclusion, despite the fact that the genetic architecture of obesity has just begun, the results obtained so far suggest that a great number of genes, loci, or chromosomal regions distributed on different chromosomes could play a role in determining body fat and fat distribution in humans.

This reflects the complex and heterogeneous nature of obesity. The accumulation of adipose tissue in the abdominal region is at least partially influenced by genes, which becomes more evident as the number of involved genes are identified.

The concept that adipocytes are secretory cells has emerged over the past few years. Adipocytes synthesize and release a variety of peptide and nonpeptide compounds; they also express other factors, in addition to their ability to store and mobilize triglycerides, retinoids, and cholesterol.

These properties allow a cross-talk of adipose tissue with other organs as well as within the adipose tissue. The important finding that adipocytes secrete leptin as the product of the ob gene has established adipose tissue as an endocrine organ that communicates with the central nervous system.

As already mentioned, LPL is the key regulator of fat cell triglyceride deposition from circulating triglycerides. LPL is found, after transcytosis, associated with the glycosaminoglycans present in the luminal surface of the endothelial cells. The regulation of LPL secretion, stimulated by the most important hormonal regulator, insulin, is related to posttranslational changes in the LPL enzyme, at the level of the Golgi cisternae and exocytotic vesicles, insulin possibly having a positive role in this secretory process Genes encoding LPL were not differentially expressed in omental when compared with subcutaneous adipocytes However, in very obese individuals omental adipocytes express lower levels of LPL protein and mRNA than do subcutaneous fat cells The regulation of LPL in obesity has been presented in the Section on correlations of abdominal visceral fat.

With respect to the hormonal regulation of LPL, insulin and glucocorticoids are the physiological stimulators of the LPL activity, and their association plays an important role in the regulation of body fat topography.

In effect, omental adipose tissue is known to be less sensitive to insulin, both in the suppression of lipolysis and in the stimulation of LPL However, when exposed to the combination of insulin plus dexamethasone in culture for 7 days, large increases in adipose LPL were observed because of increases in LPL mRNA Significant differences were observed between men and women.

The increase in LPL in response to dexamethasone suggests that the well known steroid-induced adipose redistribution especially in the abdomen may be caused by increases in LPL, which would lead to a preferential distribution of plasma triglyceride fatty acids to the abdominal depot.

Therefore, these data suggest that LPL is central to the development of abdominal visceral obesity On the other hand, catecholamines, GH, and testosterone in males reduce adipose tissue LPL Acylation-stimulating protein ASP.

ASP is considered the most potent stimulant of triglyceride synthesis in human adipocytes yet described. Its generation is as follows Human adipocytes secrete three proteins of the alternate complement pathway: C3 the third component of the complement , factor B, and factor D adipsin , which interact extracellularly to produce a amino-terminal fragment of C3 known as C3a.

Excess carboxypeptidases in plasma rapidly cleave the terminal arginine from C3a to produce the amino acid peptide known as C3a desarg or ASP, which then acts back upon the adipocyte, causing triglyceride synthesis to increase.

As fatty acids are being liberated from triglyceride-rich lipoproteins and chylomicrons as the result of the action of LPL, ASP is also being generated and triglyceride synthesis increased concurrent with the need to do so. In human adipose tissue, in the postprandial period, ASP secretion and circulating triglycerides clearance are coordinated in accordance with the suggestion that ASP in sequence to LPL would have a paracrine autoregulatory role.

The adipsin-ASP pathway, therefore, links events within the capillary space to the necessary metabolic response in the subendothelial space, thus avoiding the excess buildup of fatty acids in the capillary lumen.

The generation of ASP is triggered by chylomicrons. While insulin decreases gene expression of C3, B, and adipsin, it enhances the secretion of ASP as expected from the concurrent action of LPL and ASP. However, more intensely and independent of insulin, ASP is capable of stimulating triglyceride synthesis in adipocytes and fibroblasts.

Thus, from the reduced sensitivity to insulin in the suppression of lipolysis and stimulation of LPL by the omental adipose tissue, omental obesity may represent an example of impaired activity of the ASP pathway even if dysfunction of the pathway is a secondary feature.

As a consequence, omental adipose tissue, as compared with subcutaneous fat tissue, would have a limited capacity to prevent fatty acids from reaching the liver, which may contribute to the abnormalities in metabolism observed in visceral obesity Cholesteryl-ester transfer protein CETP.

Human adipose tissue is rich in CETP mRNA, probably one of the major sources of circulating CETP in humans. CETP promotes the exchange of cholesterol esters of triglycerides between plasma lipoproteins. In this way, the adipose tissue is a cholesterol storage organ in humans and animals; peripheral cholesterol is taken up by HDL species, which act as cholesterol efflux acceptors, and is returned to the liver for excretion , The few studies of circulating CETP in obesity have shown that activity and protein mass of CETP are both significantly increased in obesity, being negatively correlated with HDL cholesterol and the cholesteryl ester-triglyceride ratio of HDL2 and HDL3, thus exhibiting an atherogenic lipoprotein profile.

Furthermore, there was a positive correlation with fasting plasma insulin and blood glucose, suggesting a possible link to insulin resistance — From an observation of Angel and Shen , it could be suggested that the CETP activity of omental adipose tissue is greatly increased in comparison with subcutaneous fat.

Retinol-binding protein RBP. Adipose tissue is importantly involved in retinoid storage and metabolism. RBP is synthesized and secreted by adipocytes , the rate of RBP gene transcription being induced by retinoic acid The mRNA encoding RBP is expressed at a relatively high level in adipocytes with no difference between subcutaneous and omental fat cells There are no data regarding retinol mobilization from adipose stores in humans; however, in vitro studies with murine adipocytes showed that the cAMP-stimulated retinol efflux from fat cells was not the result of increased RBP secretion but instead due to the hydrolysis of retinyl esters by the cAMP-dependent hormone-sensitive lipase PAI-1 is a serine protease inhibitor and evidence suggests that it is a major regulator of the fibrinolytic system, the natural defense against thrombosis.

It binds and rapidly inhibits both single- and two-chain tissue plasminogen activator tPA and urokinase plasminogen activator uTPA , which modulate endogenous fibrinolysis. The major sources of PAI-1 synthesis are hepatocytes and endothelial cells, but platelets, smooth muscle cells, and adipocytes are also contributors The increased gene expression and secretion of PAI-1 by adipose tissue contribute to its elevated plasma levels in obesity, presenting a strong correlation with parameters that define the insulin resistance syndrome, in particular with fasting plasma insulin and triglycerides, BMI, and visceral fat accumulation: omental adipose tissue explants produced significantly more PAI-1 antigen than did subcutaneous tissue from the same individual, and transforming growth factor-βl increased PAI-1 antigen production In a premenopausal population of healthy women with a wide range of BMI, there was a positive correlation of PAI-1 activity with CT-measured visceral fat area, independent of insulin and triglyceride levels.

Weight loss confirmed this link. PAI-1 diminution was correlated only with visceral adipose tissue area loss and not with total fat, insulin, or triglyceride decrease Results from in vitro studies have shown that insulin — stimulates PAI-1 production by cultured endothelial cells or hepatocytes.

Attempts to extrapolate these in vitro data to in vivo proved difficult. Acute 2-h hyperinsulinemia modulation of plasma insulin in humans did not affect PAI-1 levels, and hypertriglyceridemia from several origins was not always associated with increased PAI-1 levels In the same way, exogenous short-term insulin infusion with triacylglycerol and glucose failed to demonstrate elevations of PAI-1 The augmentation of PAI-1 by insulin probably requires concomitant elevation of lipids and glucose and perhaps other metabolites in blood, as suggested by the strikingly synergistic effects when Hep G2 cells are exposed to both insulin and fatty acids in vitro Accordingly, a hyperglycemic hyperinsulinemic clamp associated with an intralipid infusion for 6 h, to induce hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia, produced an increase in PAI-1 concentrations in blood for as long as 6 h after cessation of the infusion However, the extent to which elevation of any one constituent or any given combination of elevations is sufficient to induce the phenomenon has not yet been elucidated in insulin-resistant patients.

In effect, the reduction of PAI-1 after weight loss related more to the degree of weight reduction than to triglyceride or insulin changes, as above indicated, and the lack of increase of PAI-1 in type 2 diabetics without obesity , strongly suggesting that visceral fat is an important contributor to the elevated plasma PAI-1 level observed in visceral obesity independent of insulin, triglyceride, and glucose level.

Finally, prospective cohort studies of patients with previous myocardial infarction or angina pectoris have underlined the association between an increase in plasma PAI-1 levels and corresponding defective fibrinolysis and the risk of atherosclerosis and thrombosis, particularly in relation to coronary events , thus linking visceral fat accumulation to macrovascular disease Recently, it was shown that in addition to insulin, corticosteroids dexamethasone and hydroxycorticosterone affect PAI-1 synthesis by human subcutaneous adipose tissue explants in a dose-dependent manner; this model showed the regulation of PAI-1 by adipose tissue after validation by showing a high correlation between the production of PAI-1 by omental and subcutaneous fat In the same way, it was demonstrated that PAI-1 production was significantly correlated with that of tumor necrosis factor-α TNFα , emphasizing a possible local contribution of TNFα in the regulation of PAI-1 production by human adipose tissue P aromatase activity in adipose tissue is important for estrogen production, which may have a paracrine role, since, as previously indicated, estrogen receptors are expressed in human adipose tissue In effect, estrone, the second major human circulating estrogen in premenopausal women and the predominant one in postmenopausal women, is mostly derived from the metabolism of ovarian-secreted estradiol catalyzed by 17β-hydroxy steroid dehydrogenase and from aromatization of androstenedione in adipose tissue in the former and almost exclusively by aromatization of that C19 androgen secreted by the adrenals in the latter.

The peripheral aromatization of testosterone to estradiol and estrone contributes minimally to estradiol and estrone production The conversion rate of androstenedione to estrone increases as a function of aging and obesity [due to an increase in adipose tissue P aromatase transcript levels, highest in the buttocks, next highest in the thighs, and lowest in the subcutaneous abdominal tissue , ] and significantly greater in women with lower gynoid obesity than in upper body obesity In obese men, the peripheral conversions of testosterone to estradiol and androstenedione to estrone, as well as the circulating levels of those estrogens, are also increased in proportion to the degree of obesity , However, only plasma levels of estrone had a significant correlation with CT-derived abdominal visceral fat and femoral areas Since the increased metabolism of testosterone to estradiol did not account for the major increase in estradiol production in obese men , it is probable that estradiol is secreted or is produced from the peripheral conversion of estrone, as observed in postmenopausal women.

The most abundant adrenal steroid, dehydroepiandrosterone sulfate DHEA-S can also form the active sex steroids, dihydrotestosterone and estradiol, in several tissues, including mesenteric fat The active androgens and estrogens made locally in peripheral tissues, especially adipose fat, exert their action by interacting with the corresponding receptors in the same or nearby cells where their synthesis took place before being released in the extracellular environment as such or as inactive metabolites.

The aromatase enzyme responsible for transforming androstenedione into estrone is present in nonendocrine tissues, particularly adipocytes and adipose stromal cells, the level of aromatase activity in stromal cells being greater than that in adipocytes Insulin and cortisol independently induce preadipocyte differentiation with both having a synergistic effect The intrinsic gender differences in preadipocytes could contribute to a gender-specific pattern of fat distribution Leptin is the product of the obesity ob gene, which is expressed in adipocytes , The human ob gene spans approximately 20 kb and exists in a single copy on chromosome 7q Several studies in rodents suggest that leptin acts as a signaling factor from adipose tissue to the central nervous system, regulating food intake and energy expenditure.

It is hypothesized that via this leptin feedback loop, homeostasis of body weight and a constant amount of body fat are achieved In humans, a strong positive correlation is observed between serum leptin levels and the amount of body fat and adipocyte leptin mRNA as in rodents , The results are in accordance with the in vitro data indicating that leptin secretion is a reflection of fat hypertrophy.

The adipocyte is the only known source of the ob gene product, leptin, as the preadipocytes do not present this capacity The subcutaneous-omental ratio of leptin mRNA expression was markedly higher in women than in men. Part of the results, according to the authors, could be explained, particularly in women, by the fact that subcutaneous adipocytes are larger than omental adipocytes and as adipocytes increase in size, the leptin mRNA is up-regulated such that it forms a greater proportion of the total mRNA than in smaller adipocytes.

Indeed, increased leptin mRNA expression in large adipocytes has been reported by Hamilton et al. Furthermore, leptin expression and levels increase as the size of the adipose tissue triglyceride stores increase In a study examining the secretion of leptin in subcutaneous and omental fat tissue from obese and nonobese women, it was shown that the leptin secretion rate and leptin mRNA expression were about 2 to 3 times higher in the subcutaneous than in the omental fat tissue in both obese and nonobese subjects.

There was a positive correlation between BMI and leptin secretion rates in subcutaneous and omental fat tissue. Furthermore, leptin secretion rates in both fat tissues had a high positive correlation with serum leptin levels.

Serum leptin circulates, in part, bound to transport proteins in the serum of both rodents and humans, and the size distribution of endogenous serum leptin, as determined by RIA after sucrose gradient centrifugation, is consistent with saturation of binding in hyperleptinemic obesity.

Thus, in humans, free leptin increases with BMI For individuals with the same BMI, the leptin circulating levels can vary by 1 order of magnitude , suggesting that leptin is regulated by factors other than the size of the adipose tissue depot. In effect, the secretion of leptin by adipocytes is regulated by nutritional and hormonal factors.

Acute changes in energy balance appear to regulate leptin expression and circulating levels. On the other hand, both leptin expression and levels decline rapidly in response to starvation, with serum leptin levels starting to decline after 12 h of fasting and reaching a nadir after 36 h, out of proportion to body adiposity changes , Thus, under conditions of steady-state energy balance, leptin is a static index of the amount of triglyceride stored in adipose tissue and in non-steady-state energy balance situations.

Leptin may be acutely regulated independently of the available adipose tissue triglyceride stores and may serve as a sensor of energy balance However, the precise mechanism mediating the distinct responses to changes in body adiposity and energy balance remains to be elucidated.

In rodents, the decreased ob gene expression after fasting and increase after realimentation appear to be related, according to in vitro data, to a transcriptional direct effect of insulin , , In humans, the positive effects of insulin are controversial in vivo.

Experiments in vitro have not solved the controversy over the potential effects of insulin on leptin synthesis, as both an increase and no change have been reported Dose-response and time-course characteristics of the effect of insulin on plasma leptin in normal men during a 9-h euglycemic clamp indicated that physiological insulinemia acutely increases leptin by comparison with a control saline infusion.

Plasma leptin also showed a dosage-dependent increase during the insulin infusion The hormonal regulation glucocorticoids and insulin of leptin synthesis was studied by Halleux et al. They found that glucocorticoids, at physiological concentrations, stimulated leptin secretion by enhancing the pretranslational machinery in human visceral fat.

This effect was more pronounced in obese subjects due to a greater responsiveness of the ob gene. Unlike glucocorticoids, insulin had no direct stimulatory effect on ob gene expression and leptin secretion and even prevented the positive response to dexamethasone by a cAMP-independent mechanism that remained functional despite insulin resistance.

Serum leptin concentrations in humans exhibit a sexual dimorphism, with circulating levels being higher in women than in men.

Although women tend to have a higher fat mass than men for the same BMI, this dimorphism appears to occur independently of body adiposity Two factors are related to the sexual dimorphism of serum leptin. The first is the higher ratio of subcutaneous to omental fat mass 7 and since a significantly higher subcutaneous-omental fat ratio of leptin expression was demonstrated in women, as above indicated , the higher serum leptin levels in women could reflect, at least partially, these gender variations in regional body fat distribution and leptin expression.

The second factor is the prevailing sex steroid milieu. Cross-sex hormone administration in transsexual subjects showed that subjects with high circulating testosterone, whether male or female, had significantly lower serum leptin at a certain degree of body fatness compared with subjects male or female with high estrogen and low testosterone levels.

These results indicated that sex hormone steroids, in particular testosterone, play an important role in the regulation of serum leptin levels, concluding that the prevailing sex steroid milieu, not genetic sex, is the significant determinant of the sex difference in serum lipids It was shown that TNFα positively modulates leptin secretion by adipocytes ; thus, increased TNFα expression in adipose cells seen in obesity could be related to the hyperleptinemia found in this situation.

In effect, a positive independent association was shown between circulating levels of leptin and of circulating soluble human kDa TNFα receptor, which has been validated as a sensitive indicator of activation of the TNFα system in healthy young controls and type 2 diabetics.

This reflects an association between leptin and the TNFα system in humans similar to that seen in rodents, where TNFα and interleukins increase leptin gene expression and circulating leptin levels , All experimental studies indicated that the central nervous system is a major site of leptin action, inducing a reduction in activity of orexigenic and an activation of anorexigenic neurons , Moreover, leptin may affect neuroendocrine mechanisms other than regulation of food intake, which will not be discussed in the present review.

Furthermore, it is being increasingly appreciated that leptin may also act in the periphery. Thus, leptin has been shown to reduce lipid synthesis in cultured adipocytes as well as decrease triglyceride synthesis and increase fatty acid oxidation in normal pancreatic islet cells in short-term culture Normal rats made chronically hyperleptinemic exhibit a prompt and sustained reduction in food intake and disappearance of all visible body fat, associated with hypoglycemia, as well as hypoinsulinemia associated with complete depletion of islet cell triglyceride content, unresponsive to in vitro stimulatory levels of glucose and arginine.

It was concluded that hyperleptinemia causes reversible β-cell dysfunction by depleting tissue lipids, thereby depriving β-cells of a lipid signal required for the insulin response to other fuels This finding, in combination with the previous observation that insulin stimulates leptin secretion and the demonstration of leptin receptors on human islets β-cells, and that leptin suppresses insulin secretion and gene expression, suggests the existence of an adipoinsular axis in rodents and humans in which insulin stimulates leptin production in adipocytes, and leptin inhibits the production of insulin in β-cells There are also actions of leptin on other organ systems, apart from the nervous system and endocrine-metabolic realms.

Angiotensinogen is synthesized primarily by the liver and secreted abundantly by the adipose tissue. Its gene expression in fat tissue is regulated by glucocorticoids and cleaved in the circulation by renin to angiotensin I, which is subsequently converted to angiotensin II by angiotensin-converting enzyme; both enzymes are also expressed in adipose tissue Thus, angiotensin II, produced locally in adipose tissue, can induce preadipocytes to differentiate into adipocytes by stimulating prostacyclin production from adipocytes It was found that in nonobese and obese rats, angiotensinogen protein and correspondent mRNA are about 2-fold higher in visceral adipose tissue than in subcutaneous sites, and its production increases concomitantly with the development of obesity in the obese Zucker rat , Since adipose tissue constitutes the most important source of angiotensinogen after the liver, it cannot be excluded that, in addition to its effect on the development of adipose tissue, an enhanced secretion of angiotensinogen, via angiotensin II, could lead to the increased levels of blood pressure frequently observed in obesity The angiotensinogen mRNA expressed in subcutaneous abdominal adipocytes was greater in obese than in lean subjects, but not significantly so.

Further, no significant differences were found between obese patients with and without hypertension in the small numbers of subjects studied Through an extensive search of the human adipose tissue cDNA library, Matsuzawa and co-workers isolated a novel cDNA encoding a collagen-like secretory protein that was named adiponectin.

Adiponectin was demonstrated to be specifically and abundantly expressed in adipose tissue; it is detected in human plasma and analyzed in both by immunoblotting.

In normal male subjects, plasma adiponectin levels were negatively correlated with BMI and visceral fat area but not with subcutaneous abdominal fat area.

Plasma levels in patients with coronary heart disease were lower than those without heart disease, although no difference was observed in BMI or visceral fat area To elucidate the regulation of plasma adiponectin in comparison with leptin levels, the same investigators studied rhesus monkeys with various body weights and also with and without type 2 diabetes.

There was a significant inverse correlation between body weight and plasma adiponectin levels while, as expected, corresponding leptin levels correlated significantly with body weight.

With respect to the insulin values, the plasma adiponectin decreased and leptin increased significantly in hyperinsulinemic monkeys. A longitudinal study in 13 monkeys revealed that the plasma adiponectin decreased as they gained weight, whereas the plasma leptin levels increased.

It was concluded that the adiponectin levels would be negatively regulated by adiposity and that the plasma leptin levels were positively regulated by adiposity It was shown that adiponectin inhibited growth factor-induced human aortic smooth muscle cell proliferation Adipocytes are both a source of and a target tissue of the cytokine TNFα, which is absent in the preadipocyte although it is expressed in the adipocyte.

Obese individuals express 2. Similar increases were observed in adipose production of TNFα protein. In obese subjects, high circulating levels were reported, which fell significantly after weight loss In addition, a strong positive correlation is observed between TNFα mRNA expression in fat tissue and the level of hyperinsulinemia, an indirect measure of insulin resistance.

Regarding the molecular mechanism responsible for the decreased insulin action, especially in obesity, it appears to involve TNFα-induced serine phosphorylation of insulin-receptor-substrate- IRS -1 Although there was heterogeneity in mRNA values among obese subjects, there was a consistent reduction in TNFα mRNA expression and protein level of approximately the same magnitude in adipose tissue after weight loss.

In contrast to the marked site-related expression of leptin, as previously indicated, genes encoding TNFα are not differentially expressed in human subcutaneous and omental adipocytes Since the expression of TNFα is negatively correlated with LPL activity in the adipose tissue and is higher in the reduced-obese subjects, the magnitude of these changes did not correlate with each other, suggesting that factors, other than adipocyte TNFα expression, are involved in regulating LPL in the reduced-obese state Together, these studies could suggest a local action of the cytokine, in addition to the existence of some additional local factor, limiting the entrance of fatty acids via LPL and the subsequent hypertrophy of the adipocyte.

In effect, in addition to the decrease in activity of LPL, TNFα has multiple actions in adipose tissue, including a decrease in expression of the glucose transporter GLUT 4 and an increase in hormone-sensitive lipase In a group of male patients with premature coronary heart disease, TNFα levels measured using a sensitive enzyme-linked immunosorbent assay ELISA for human TNFα did not show any relationships either with plasma insulin concentrations or the degree of insulin resistance as measured by the HOMA method a crude measure of insulin resistance.

It appeared from that study that the elevated TNFα circulating levels were associated with atherogenic metabolic disturbances in men with premature coronary heart disease In line with this report is the observation that in subcutaneous adipose tissue taken from lean controls, obese insulin-resistant subjects with normal glucose tolerance, and obese insulin-resistant type 2 diabetics, all males, TNFα mRNA expression was normal in healthy obese men and type 2 diabetic patients; it was not regulated by hyperinsulinemia and was not associated with obesity or insulin resistance, as evaluated by an euglycemic hyperinsulinemic clamp Accordingly, given the well established link between omental adiposity and insulin resistance in humans, if adipocyte TNFα expression is linked to insulin resistance , there should be evidence for a site-related TNFα expression in isolated human adipocytes that has not been observed In addition, Montague et al.

Analysis of the data presented by Kern et al. In addition, preliminary data indicated a trend for a higher release of TNFα in omental than subcutaneous adipose tissue obtained from morbidly obese subjects PPARs are ligand-activated transcription factors of the nuclear hormone receptor superfamily.

Of the three distinct PPAR subtypes, PPAR-γ is highly tissue selective, being most abundant in adipose tissue. PPAR-γ exists in three isoforms, γ-1, -2, and The nature of the endogenous ligand s to PPAR-γ is still unclear, although arachidonic acid metabolites such as deoxy-δ,PGJ 2 , and long-chain fatty acids have been implicated.

Activation of PPAR-γ results in altered expression of selected target genes. PPARs, including PPAR-γ, are only transcriptionally active after heterodimerization with a 9- cis retinoic acid-activated receptor, retinoid X receptor RXR.

Such sequences have been identified in the regulatory regions of PPAR-γ-responsive genes[ e. In a comparison of the mRNA expression levels of PPAR-γ in subcutaneous and omental adipose tissue, Lefebve et al. When the absolute PPAR-γ mRNA values were analyzed, there was no relation with BMI in subcutaneous adipose tissue.

In the omental fat, however, a trend to a positive correlation was observed but it did not reach significance in the population tested, who exhibited a wide range of BMI.

The same researchers found a 2-fold reduction in GLUT 4, glycogen synthase, and leptin mRNA expression in omental adipose tissue, suggesting a lower GLUT 4-mediated glucose uptake, and perhaps glucose storage, in omental adipocytes while the total insulin receptor expression was significantly higher in this tissue.

Most of this increase was accounted for by expression of the differentially spliced insulin receptor lacking exon 11, which is thought to transmit the insulin signal less efficiently than the insulin receptor lacking exon This finding is consistent with the reduction in GLUT 4 and glycogen synthase but partially at least for the decrease in leptin gene expression.

This suggests that other regulators of that gene are more likely to participate in the depot-specific difference. With respect to the expression of PPAR-γ splice variants, γ-1 andγ -2, it was demonstrated that PPAR-γ-l is the major isoform in human adipocytes by Western blotting However, Vidal-Puig et al.

On the other hand, Auboeuf et al. In addition, the expression of PPAR-γ isoforms is modulated by caloric intake, i. The two adipogenic hormones, insulin and glucocorticoids, show a synergistic effect to induce PPAR-γ mRNA after in vitro exposition to isolated human adipocytes.

In vivo modulation of human PPAR-γ mRNA by obesity and nutrition could suggest a possible role for PPAR-γ expression in the pathogenesis of altered adipocyte number and function in obesity In effect, PPAR-γ has been shown to induce apoptosis of large adipocytes and the differentiation of small adipocytes in vivo Because smaller adipocytes are usually more sensitive to insulin, such a differentiated response would be expected to produce greater insulin-dependent glucose uptake.

Increasing evidence points to the importance of locally produced cytokines in the regulation of adipocyte metabolism. Among the cytokines, in addition to TNFα, which increases with fat cell enlargement in obesity, adipose tissue also produces another ubiquitous cytokine, interleukin Since the plasma concentration of interleukin-6 is proportional to the fat mass , the adipose tissue could become an important source of that cytokine.

Since interleukin-6 as well as TNFα reduces the expression of LPL, it could have a local role in the regulation of the uptake of fatty acids by the adipose tissue.

It is possible that adipose tissue TNFα, whose expression is increased in obesity, induces adipocyte and nonadipocyte interleukin-6 expression. In effect, TNFα produces a fold increase in interleukin-6 production in differentiated 3T3-L1 adipocytes It was demonstrated that fragments of omental adipose tissue release 2—3 times more interleukin-6 than subcutaneous abdominal adipose tissue, both obtained from severely obese subjects undergoing obesity surgery.

Adipocytes isolated from the omental depot also secrete more interleukin-6 than those from the subcutaneous depot, but other cells within the adipose tissue made a greater contribution to the high release of that cytokine Thus, interleukin-6 may be both an autocrine and a paracrine regulator of adipocyte function in addition to possible effects on other tissues, as stimulation of such acute phase protein synthesis and stimulation of the hypothalamic-pituitary-adrenal axis Because the venous drainage from omental tissue flows directly into the liver, the metabolic impact of interleukin-6 release from omental adipose tissue may be of particular importance, since that cytokine increases hepatic triglyceride secretion , and may, therefore, contribute to the hypertriglyceridemia associated with visceral obesity.

It was demonstrated that cultures of adipose tissue from omental and subcutaneous adipose tissue with glucocorticoids down-regulate the production of interleukin Since interleukin-6 directly stimulates adrenal cortisol release in addition to stimulating hypothalamic CRH and pituitary ACTH release , adipose tissue interleukin-6 may, therefore, act as a feedback regulator of hypothalamic-pituitary axis function.

Cortisol suppression of adipose interleukin-6 production may serve as a feedback inhibitor of this regulatory loop , taking into consideration that increased cortisol turnover is a feature of visceral obesity, as will be discussed later in this review.

Insulin-like growth factor-1 IGF-I. It was shown in preadipocytes from human subcutaneous fat tissue that adipose differentiation induced by the addition of cortisol, insulin, and l-T 3 to a serum-free culture medium was associated with an increase in IGF-I and IGF-binding protein 3 IGFBP3 mRNAs, while the expression of IGF-I receptor IGF-IR mRNA remained relatively stable and the production of IGF-I and IGFBP3 increased greatly.

In preadipocytes, human GH stimulated IGF-I and IGFBP3 mRNA expression as well as an increase in IGF-I and IGFBP3 production, possibly increasing the disposal of free IGF-I.

In differentiated adipocytes, human GH stimulated the expression and production of IGFBP3 but not of IGF-I, possibly decreasing the disposal of free IGF-I. The presence of cortisol led to a decrease of IGFBP3 expression and production in adipocytes.

In addition, it was shown that in human adipocytes IGF-1R is expressed in preadipocytes Uncoupling proteins UCPs.

UCPs are mitochondrial membrane transporters that are involved in dissipating the proton electrochemical gradient, thereby releasing stored energy as heat.

This implies a major role for UCPs in energy metabolism and thermogenesis, which are key risk factors for the development of obesity and other eating disorders.

At present, three different UCPs have been identified by gene cloning: UCP-1 is expressed in brown adipocytes in rodents inducing heat production by uncoupling respiration from ATP synthesis; UCP-2 is widely expressed in human tissues; and UCP-3 expression is primarily limited to skeletal muscle, an important mediator of thermogenesis in humans Using competitive RT-PCR as a measure, UCP-1 mRNA expression in the visceral adipose tissue of morbidly obese subjects was found to be at significantly lower levels in comparison to controls.

In obese patients, UCP-1 mRNA levels exhibited a strong association with the UCP-1 promoter polymorphism, which was in complete association with four substitutions. Furthermore, there was a borderline significant association of UCP-1 mRNA abundance and the combined effect of Arg64Trp and Gln28Glu substitution of the β 3 - and β 2 -adrenergic receptor, respectively; the mutation of the β 3 -adrenoreceptor was associated with lower lipolytic activity, suggesting that variant forms of adrenergic receptors implicated in obesity may affect UCP-1 expression Kogure et al.

However, genetic analysis of various human cohorts suggested a weak contribution of UCP-1 to control fat content and body weight Oberkofler et al.

have also demonstrated reduced UCP-2 mRNA expression levels in visceral adipose tissue in morbid obesity in comparison with control lean subjects. In both obese and nonobese individuals, UCP-2 mRNA abundance was higher in the intraperitoneal than in the extraperitoneal fat tissue, the UCP-2 mRNA expression not being significantly different between obese and nonobese subjects in the latter In conclusion, the reduction of UCP-1 and -2 mRNA in visceral adipose tissue associated with reduced gene expression of UCP-2, but not UCP-3, in skeletal muscle of human visceral obesity is compatible with a decreased capacity to expend energy in subjects with visceral obesity.

The data indicating that UCP-2 and UCP-3 are involved in energy or proton conductance activities in humans are still quite weak, and the biochemical activities and biological roles of these newly described UCPs remain to be elucidated.

In addition to the secreted ubiquitous angiogenic factors TGFβ and PGE 2 , monobutyrin l-butyryl-glycerol is a specific secretion product of the adipocyte, favoring the vascularization of adipose tissue on development and vasodilation of the microvessels As clearly indicated earlier in this review, individuals with upper-body central obesity, i.

e , fat accumulation in the subcutaneous abdominal and visceral depots, are prone to metabolic and cardiovascular complications, especially when there is excess fat in the visceral area. What is the mechanism behind regional fat distribution, and why is it more dangerous to accumulate fat in the visceral area than in other regions?

The vascular anatomy and the metabolic activity of visceral fat may be the key factors predisposing to complications of obesity Only visceral adipose tissue is drained by the portal venous system and has a direct connection with the liver. Mobilization of FFAs is more rapid from visceral than from subcutaneous fat cells because of the higher lipolytic activity in visceral adipocytes, in both nonobese and obese individuals, particularly in the latter, which probably contributes significantly to the FFA levels in the systemic circulation The higher lipolytic activity in visceral fat in comparison with the subcutaneous adipose tissue can be attributed, as indicated previously, to regional variation in the action of the major lipolysis-regulating hormones, catecholamines and insulin, the lipolytic effect of catecholamines being more pronounced and the antilipolytic effect of insulin being weaker in visceral than in subcutaneous adipose tissue This site variation is related to the increased expression and function of β-adrenoreceptors particularly β 3 associated with a decreased function of α 2 -adrenoreceptor-dependent antilipolysis in the obese and a decreased insulin receptor affinity and signal transduction in visceral adipocytes Table 3.

With respect to the antilipolytic effect of adenosine and prostaglandins produced in adipose tissue, it is equally or slightly more pronounced in subcutaneous than in visceral adipocytes because of decreased agonist receptor number in visceral adipocytes The visceral fat catecholamineinduced lipolysis is greater in obese men than in women; this is partially due to a larger fat cell volume and also to a greater β 3 - and lowerα 2 -adrenoreceptor sensitivity , which results in higher FFA mobilization from visceral fat to the portal system in men than in women.

On the other hand, the antilipolytic effect of insulin is reduced in omental adipocytes regardless of the presence of obesity Table 3. Thus, the enhanced total lipolytic activity probably contributes significantly to the FFA levels in systemic circulation However, in obesity, changes occur in adipocytes that conceivably try to offset the detrimental effects of accelerated lipolysis.

For instance, although the lipolytic response to catecholamines is increased, the sensitivity of abdominal subcutaneous fat to catecholamine-induced lipolysis is decreased in obese women because of a depletion of β 2 -adrenoreceptors This adaptive mechanism of subcutaneous fat cannot be detected in visceral fat of obese individuals, in whom there are normal sensitivities of β 1 and β 2 -adrenoreceptors but markedly increased sensitivity of β 3 -adrenoreceptor-dependent lipolysis and severely decreased sensitivity toα 2 -dependent antilipolysis Table 3.

With respect to the size of the fat depots with relation to LPL activity as well as acylation-stimulating protein as indicated in the adipose tissue LPL activity in Section IV , it was demonstrated, as previously shown 21 , that the uptake of triglycerides is higher in intraabdominal fat and, combined with rapid rate of release of glycerol, is a measurement of lipid mobilization.

This is independent of the degree of BMI, and without correlation with LPL activity, which is expressed equally in human subcutaneous and omental adipocytes In women, but not in men, the omental adipose tissue has smaller adipocytes, and it presents lower LPL activity than subcutaneous fat depots.

The LPL activity is lower in visceral than in subcutaneous fat irrespective of the presence of obesity Table 3. Obesity adds a generalized increase in lipid turnover sustained by an increased response to lipolytic agents, a reduced effect of antilipolytic hormones, and increased LPL activity, which is most likely due to chronic hyperinsulinemia and playing a role in maintaining excess body fat depots Table 3.

Thus, the visceral fat mass probably contributes significantly to the FFA levels in the systemic circulation However, the elevated exposure of the liver to FFAs from visceral fat in obesity was deduced indirectly rather than measured directly.

Available information does not indicate that visceral adipose tissue contributes much to liver exposure of FFA There is, however, a possibility that, by the addition of portal FFA and FFA in the hepatic artery, the liver is exposed to more than would be predicted from systemic FFA availability data , The elevated FFA flux into the liver would decrease the hepatic insulin extraction by inhibiting insulin binding and degradation , leading to systemic hyperinsulinemia as well as inhibiting the suppression of hepatic glucose production by insulin , In addition, FFAs accelerate gluconeogenesis by providing a continuous source of energy ATP and substrate Finally, in response to the increase in FFA availability, an increased esterification of FFAs and reduced hepatic degradation of apolipoprotein B lead to an increased synthesis and secretion of small VLDL particles Fig.

Furthermore, central obesity with insulin resistance and increased FFA levels is associated with increased hepatic lipase activity, which leads to removal of lipids from LDL and HDL, making them smaller and more dense.

Thus, hepatic lipase activity is a major determinant of LDL size and density and the amount of HDL 2 cholesterol Factors regulating the abdominal fat distribution.

Wajchenberg et al. In addition to the effects on the liver, the increase in FFA flux induces a decrease in insulin-stimulated peripheral primarily in skeletal muscle, the most relevant site of insulin resistance glucose disposal, which in normal subjects is compensated by FFA-induced potentiation of glucose-stimulated insulin secretion With the associated reduction in hepatic insulin extraction, this would determine still greater peripheral hyperinsulinemia Fig.

With hyperinsulinemia, which nevertheless inhibits lipolysis of insulin-sensitive subcutaneous adipocytes, the fraction of systemic FFAs originating in visceral fat may be further expanded In obese individuals who are genetically predisposed to develop type 2 diabetes, FFAs may eventually fail to stimulate insulin secretion sufficiently, leaving hepatic and peripheral insulin resistance unchecked and resulting in hepatic glucose overproduction and peripheral underutilization of glucose.

In contrast to the originally postulated mechanism in which FFAs were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase , more recent studies have demonstrated that FFAs induce insulin resistance in obesity and type 2 diabetes by initial inhibition of glucose transport.

In relation to the hyperinsulinemia of obesity, as reviewed by Boden , numerous studies have demonstrated that elevated release of FFA from adipose tissue inhibits insulin-stimulated glucose utilization, as indicated above.

In addition, the accumulation of triglyceride in muscle has been linked to impaired glucose disposal Also, the failure to normally suppress postprandial FFA availability in individuals with upper body obesity despite a significantly greater postprandial insulinemic response than lower body obese and nonobese subjects might impair the ability of insulin to suppress hepatic glucose output and stimulate glucose uptake in this particular phenotype Since insulin secretion in obese subjects appears to be particularly sensitive to circulating FFA levels, it is attractive to suppose that increased availability of FFA directly stimulates the pancreatic β-cell while concomitantly contributing to insulin resistance in such individuals.

As suggested by Unger , since FFA-induced changes in tissues increase in fatty acid acyl-CoA are proportional to the levels of FFA, the insulin resistance and insulin hypersecretion are matched and glucose tolerance is normal.

Consistent with this notion would be the correlation seen between pancreatic triglyceride content and glucose-stimulated insulin secretion in rat models with varying degrees of adiposity In effect, when obese subjects become diabetic, FFAs rise to still higher levels with proportionally higher tissue levels of FACoA fatty acid acyl CoA being reflected by greater accumulation of triglycerides.

In muscle, this intensifies insulin resistance, while islets, which respond fully to moderate FFA overload, are incapable of further increasing insulin secretion to match the peripheral insulin resistance.

The greatly increased islet FACoA impairs the ability of the β-cells to respond to postprandial hyperglycemia, the hyperinsulinemia no longer matches the increase in insulin resistance, and thus type 2 diabetes begins We have demonstrated that the overnight lowering of plasma FFA levels with the potent, long acting nicotinic acid analog acipimox could improve insulin resistance in obese subjects exhibiting a wide spectrum of insulin sensitivities ranging from normal to diabetic This suggests that basal plasma FFAs exert a physiological important effect supporting up to one half of basal insulin levels in nondiabetic and diabetic subjects and that basal plasma FFAs are responsible for some of the hyperinsulinemia in normoglycemic obese subjects The decrease in FFA was associated with an increase in insulin-stimulated glucose uptake ISGU during an euglycemic hyperinsulinemic clamp.

In contrast, in the obese nondiabetic with impaired glucose tolerance and in mild type 2 diabetes, the greater reduction in FFA was associated with an increase in GIR more than approximately 2-fold. Rates of glucose infusion needed to maintain euglycemia during hyperinsulinemic clamping GIR in lean and obese nondiabetic subjects and in subjects with IGT and type 2 diabetes after overnight treatment with placebo open bars or acipimox black bars.

Santomauro et al. All studies clearly suggest that in humans, as in rodents, glucose-fatty acid cross-talk within the β-cell is critically important for control of insulin secretion.

In addition, obesity, a condition associated with more prolonged endogenous hyperlipacidemia, has been shown to enhance β-cell dependence on circulating FFAs, resulting in basal hyperinsulinemia and increased responsiveness to a glucose load.

These findings complement other studies revealing that chronic exposure to very high levels of exogenous FFAs increases basal insulin levels and impairs glucose-stimulated insulin secretion. However, it should be emphasized that whether chronic hyperlipacidemia can actually cause impairment of β-cell function in both rodents and humans is still a matter of debate.

Several studies have demonstrated that in obesity, the regional distribution of adipose tissue is correlated strongly with a number of important metabolic variables, including plasma glucose, insulin, and lipid concentrations increased plasma total cholesterol and triglyceride and decreased plasma HDL cholesterol concentrations , as indicated in the Introduction 17 — In effect, in obese, but not lean, men and premenopausal women the adipose tissue area measured by CT was positively correlated with fasting plasma glucose and insulin and C-peptide levels and with glucose and insulin areas under the curve after a g glucose tolerance test.

In addition, it was shown that the effect of accumulation of deep abdominal fat on glucose tolerance was independent of total adiposity. On the other hand, while the subcutaneous abdominal adipose tissue area correlated significantly with the glucose area under the curve in lean and obese men but not independently from the percentage of body fat, in obese females the subcutaneous abdominal fat was not significantly correlated with the glucose area 18 , These findings, as indicated before, suggested that subjects with visceral abdominal obesity are more insulin resistant than subjects with peripheral or lower body obesity.

Indeed, Kissebah and Peiris indicated that in obese premenopausal women, a central pattern of fat distribution high WHR is associated with a greater degree of insulin resistance. Similarly, an inverse relationship between central fat content and insulin-mediated glucose disposal was found by Lillioja et al.

The same findings were presented by Park et al. However, little information is available about the relationship between body fat distribution and in vivo insulin sensitivity in nonobese subjects. In effect, Landin et al. Similarly, Bonora et al. According to these authors , such findings might be explained by the fact that in these subjects an insufficient amount of visceral fat had accumulated to exert a major impact on whole body glucose metabolism.

The subject of visceral adipose fat in individuals of normal BMI will be discussed in Section VII. Bonora and Solini et al. These authors observed that the subjects with visceral abdominal obesity, when compared with those with predominantly peripheral obesity, had significantly lower total glucose disposal, glucose oxidation, and nonoxidative glucose disposal and significantly greater lipid oxidation Fig.

Protein oxidation was positively related to glucose oxidation and negatively related to lipid oxidation. However, the rates of protein metabolism in the basal state and in the insulin concentrations encountered after a meal were normal, indicating that protein metabolism in obese patients does not differ appreciably from nonobese nondiabetic individuals.

A major finding of this study was that visceral fat was inversely related to endogenous leucine flux an index of proteolysis during hyperinsulinemia, indicating that visceral fat in obese women was associated with a greater sensitivity to the antiproteolytic effect of insulin, probably resulting from interactions between insulin and other glucoregulatory hormones, particularly anabolic steroid hormones; alternatively, higher FFA levels and the increased rate of lipid oxidation, characteristic of individuals with visceral obesity, may exert a protein-sparing effect Mean rates of total, oxidative and nonoxidative glucose disposal and lipid oxidation during an euglycemic clamp in obese women with peripheral obesity vs.

visceral abdominal obesity after controlling for the independent effect of total body fat content. In these women, as expected, visceral fat area was positively correlated to plasma FFA levels and the rate of lipid oxidation and inversely correlated to total glucose disposal, glucose oxidation, and nonoxidative glucose disposal during insulin infusion.

All these relationships were independent of total and subcutaneous fat. In a group including both nondiabetic and diabetic subjects, it was also found that the amount of visceral fat was positively and independently correlated to endogenous glucose production during insulin infusion.

As a whole, these results again suggested that an excess of visceral fat results in detrimental effects on glucose metabolism, the excess of FFA being the link between central fat and insulin resistance; however, other molecules released by visceral fat as well as other endocrine, metabolic, and hemodynamic abnormalities associated with visceral obesity might play a significant role.

Gampel B The relation of skinfold thickness in the neonate to sex, length of gestation, size at birth and maternal skinfold. Hum Biol 29— Guihard-Costa AM, Grangé G, Larroche JC, Papiernik E Sexual differences in anthropometric measurements in French newborns.

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Westrate J, Deurenberg P, van Tinteren H Indices of body fat distribution and adiposity in Dutch children from birth to 18 years of age. PubMed Google Scholar. Download references.

Gerardo Rodríguez, Mª Pilar Samper, Purificación Ventura, José L. de Ciencias de la Salud, University of Zaragoza, Spain. You can also search for this author in PubMed Google Scholar.

Correspondence to Gerardo Rodríguez. Reprints and permissions. Rodríguez, G. et al. Gender differences in newborn subcutaneous fat distribution. Eur J Pediatr , — Download citation.

Received : 26 January Accepted : 07 April Published : 27 May Issue Date : August Anyone you share the following link with will be able to read this content:.

Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Abstract The pattern and distribution of subcutaneous fat in term and preterm newborns has been assessed by skinfold thicknesses ST , describing gender and gestational age variations.

Access this article Log in via an institution. Abbreviations BS : biceps skinfold thickness CTS : central to total skinfold ratio DXA : dual energy X-ray absorptiometry FFM : fat-free mass FM : fat mass SBS : subscapular skinfold thickness SPS : suprailiac skinfold thickness ST : skinfold thickness ΣST : the sum of the four skinfolds biceps, triceps, subscapular and suprailiac TS : triceps skinfold thickness.

References Boule NG, Tremblay A, Gonzalez J, Aguilar CA, Lopez JC, Depres JP, Buchard C, Gomez JF, Castillo L, Rios JM Insulin resistance and abdominal adiposity in young men with documented malnutrition during the first year of life. Int J Obes — Article CAS Google Scholar Brambilla P, Manzoni P, Sironi S, Simeone P, Del Maschio A, di Natale B, Chiumello G Peripheral and abdominal adiposity in childhood obesity.

Int J Obes — CAS Google Scholar Butte NF, Hopkinson JM, Wong WW, Smith EO, Ellis KJ Body composition during the first 2 years of life: an updated reference.

For 10 patients it was possible to perform an additional examination 3 yr after surgery. The other 13 subjects left the study for reasons of compliance or did not show up at the scheduled 3-yr visit. The control group was examined in exactly the same way as the study group, but on only one occasion.

Subjects were examined in the morning after an overnight fast. After a min rest in the supine position, venous blood samples were drawn for the subsequent analysis of plasma glucose at the routine chemistry laboratory of the hospital.

Plasma insulin was also measured using a commercial RIA kit Amersham Pharmacia Biotech, Uppsala, Sweden. Thereafter, sc adipose tissue 1—2 g was obtained from the paraumbilical region by needle aspiration under local anesthesia using 5—10 ml 0. It has previously been demonstrated that this procedure does not influence adipocyte metabolism The tissue samples were immediately transported to the laboratory.

None of the obese subjects reported important weight changes during the 4 wk proceeding each fat biopsy. Isolated fat cells were prepared and isolated according to Rodbell In brief, adipocytes were separated from stromal cells by treatment in a shaking bath at 37 C for 60 min with 0.

Adipocyte suspensions were then rinsed three times in collagenase-free buffer using nylon filters. Fat cell sizes were measured by direct microscopy, and the mean adipocyte diameter was calculated from measurements of cells.

The total lipid weight of the incubated fat cells was determined after organic extraction. The number of fat cells incubated was determined by dividing total lipid weight by fat cell weight. The lipolysis assay has previously been described in detail The latter included noradrenaline, which is a natural nonselective α- and β-agonist; isoprenaline, a nonselective β-adrenoceptor agonist; forskolin, which stimulates adenylyl cyclase; and Bu 2 cAMP, which is a phosphodiesterase-resistant cAMP analog that stimulates the PKA-HSL complex.

After the incubation, an aliquot of the medium was removed, and glycerol, which was used as a measurement of the lipolysis rate, was analyzed using a bioluminescence method All agents caused a concentration-dependent stimulation of lipolysis that reached a plateau at the highest concentrations of agonist in each individual experiment.

The formula used to calculate cell surface area has been discussed in detail previously 10 , We calculated the rate of glycerol release at maximum effective concentration for each of the lipolytic agents used lipolytic capacity. The amount of HSL protein in adipose tissue was determined as described previously The homogenate was centrifuged at 14, rpm for 30 min, and the infranatant was removed and saved.

All steps were performed at 4 C to minimize the risk of protein degradation. The protein content in each sample was determined using a kit of reagents from Pierce Chemical Co. Rockford, IL. One hundred micrograms of total protein were then loaded on polyacrylamide gels and separated by standard SDS-PAGE.

To control for differences in gel migration, exposure time, antibody incubation, etc. Blots were blocked for 1 h in room temperature in Tris-buffered saline with 0. This was followed by an overnight incubation at 4 C in the presence of antibodies directed against HSL.

HSL antibodies were generated by one of the authors C. Secondary antibodies conjugated to horseradish peroxidase were obtained from Sigma St. Louis, MO; α-rabbit, ; α-chicken, Antigen-antibody complexes were detected by chemiluminescence using a kit of reagents from Pierce Chemical Co.

Supersignal , and blots were exposed to high performance chemiluminescence film Amersham Pharmacia Biotech. BSA fraction V, lot 63F , Clostridium histolyticum collagenase type I, forskolin, Bu 2 cAMP, and glycerol kinase from Escherichia coli G were obtained from Sigma.

Isoprenaline was obtained from Hässle Molndal, Sweden. ATP monitoring reagent containing firefly luciferase was purchased from LKBWallac, Inc.

Turku, Finland. All other chemicals were of the highest grade of purity commercially available. Data are presented as the mean ± sem and were compared using paired or unpaired t test and ANOVA. Calculations were made using the StatView software program Abacus Concepts, Berkeley, CA.

The characteristics of the study groups are presented in Table 1. At baseline obese men and women showed classical abnormalities. All of these parameters improved markedly 2 yr after bariatric surgery. The range of BMI loss after surgery was 3.

Figure 1 shows for illustrative purposes the mean concentration-response curves for noradrenaline lipolysis per cell in men and women before and 2 yr after weight loss compared with lean controls.

In all experiments noradrenaline increased lipolysis in a concentration-dependent fashion. In women the mean baseline curve of the obese subjects was elevated compared to that in lean subjects and was also normalized after weight loss.

However, in men the three mean curves did not differ much in their positions in the graph. Rate of noradrenaline-stimulated lipolysis. The individual concentration-response curves for the different lipolytic agents were analyzed for maximum effects. The group data for lipolysis per cell are given in Table 2.

Maximum stimulated lipolysis of sc adipose tissue in obese men and women before and 2 yr after bariatric surgery compared to lean controls. A, Lean controls; B, obese patients before weight loss; C, obese patients after weight loss. At 2 yr after weight reduction, basal lipolysis and maximally stimulated lipolysis in the obese female group had decreased to rates equal to those in the nonobese females.

In obese men, the basal rate of lipolysis was 2-fold elevated at baseline and was not influenced by weight reduction at the 2 yr follow-up. Maximum lipolysis induced by noradrenaline, isoprenaline, forskolin, and Bu 2 cAMP was not altered in obese men at baseline and did not change after a 2-yr weight reduction.

Group data for lipolysis were also expressed per cell surface area Table 3. Obese men showed no difference from lean men in lipolysis either before or after weight reduction, although stimulated lipolysis actually improved at a borderline significant level after the decrease in body weight.

In obese women basal lipolysis was increased at baseline and was completely normalized after weight reduction. Stimulated lipolysis was similar in obese and nonobese women, although it decreased at a borderline level of significance after surgery.

To determine whether adipocyte lipolysis was stable after weight reduction, six obese women and four obese men were followed at regular intervals until 3 yr after bariatric surgery, and adipose tissue biopsies were obtained at 0, 2, and 3 yr.

Data for basal lipolysis, Bu 2 cAMP-stimulated lipolysis, and BMI are shown in Fig. BMI decreased gradually in men and women, with the major part of the decrease occurring from 0—2 yr. In women the rate of basal and Bu 2 cAMP-induced lipolysis decreased markedly from 0—2 yr and was thereafter almost constant.

However, in men the lipolytic rates were constant from 0—3 yr. Similar results were obtained with isoprenaline and forskolin values not shown. Top , BMI of obese men and women before and 2 and 3 yr after bariatric surgery.

A comparison of lipolysis between men and women before weight loss revealed that both basal and stimulated lipolysis values per cell were significantly higher in obese women P values ranging from 0. There was no significant difference in stimulated lipolysis between genders after weight loss P values ranging from 0.

There were no important gender differences in lipolysis in nonobese subjects. The relationship between fat cell size and lipolytic capacity was examined using simple regression analysis for obese and lean patients Fig.

There were significant correlations between fat cell size and basal lipolysis both in men and women Fig. In Fig. However, these outliers responded to weight loss in the same way as the other men, and when they were omitted in statistical analysis, the results were the same as when they were included.

However, a gender difference was observed when studying maximally stimulated lipolysis. The maximum sc lipolysis induced by Bu 2 cAMP, forskolin, or isoprenaline showed a strong correlation to fat cell size in women, but there was no correlation in men.

Similar results were obtained with isoprenaline and forskolin graphs not shown. In women, the reduced basal and stimulated lipolysis values after weight reduction were distributed evenly along the same regression line as the baseline values.

Linear relationship between basal lipolysis no agent present and sc fat cell volume in obese women A , men B , and their lean controls before and after weight loss.

Linear relationship between Bu 2 cAMP-stimulated lipolysis and sc fat cell volume in obese women C and lack of correlation between Bu 2 cAMP-stimulated lipolysis and fat cell volume in obese men D. To evaluate the expression of proteins involved in lipolytic activity after weight reduction, we obtained sc adipose tissue samples from a limited set of subjects 7 men and 10 women before and after weight reduction.

The samples were run on the same Western blot 1 for men and 1 for women. To evaluate absolute amounts of detected protein we also compared sc adipose tissue from lean control subjects 8 men and 8 women with the obese samples obtained before weight reduction.

The control subjects were chosen at random. Obese and lean men were run on one Western blot, and female samples on another. Total cytosolic protein was isolated and separated by Western blotting. Immunodetection was performed with antibodies directed against HSL.

In the present study marked differences in the influence of obesity and subsequent body weight reduction on lipolysis regulation were seen between women and men. In obese women the basal rate of lipolysis as well as the lipolytic capacity measured by agents acting at various levels of the lipolytic cascade were markedly increased when expressed per fat cell.

However, lipolytic capacity per cell surface area was similar in obese and nonobese women. It is well known that the lipolytic rate in fat cells is related to fat cell size. It is very likely that the influence of obesity and weight reduction in women above all is related to changes in fat cell size, which is increased in obesity and normalized after weight reduction.

Firstly, in the whole group of women there was a strong relationship between lipolysis rate per cell and fat cell size. Secondly the rates of lipolysis per cell in adipocytes of weight-reduced obese women were distributed along the same regression line as baseline values.

In obese men the basal rate of lipolysis per cell was increased, but, in contrast to women, it was not influenced by weight reduction despite the fact that fat cell size decreased after bariatric surgery to the same extent in men as in women. The lipolytic capacity and the effect of noradrenaline on lipolysis were not influenced by either obesity or weight reduction when expressed per cell.

Furthermore, there was no relationship between lipolytic capacity per cell and fat cell size in men. Lipolysis per cell surface area was not influenced by obesity in men, although it tended to improve after weight reduction.

These data strongly indicate that obesity influences lipolysis in the sc abdominal site in a different manner in men and women.

The increased rate per cell, but not per cell surface area, observed in women indicates that obesity-mediated changes in women probably are due to the change in fat cell size. In men the increase in the basal rate of lipolysis might be a primary defect or at least more resistant to weight reduction.

It is possible that the gender difference in lipolytic capacity could be due to the fact that women adapt their lipolysis to obesity. The increase in lipolytic capacity in obese women could be a protective phenomenon.

Men do not seem to be able to increase their lipolytic capacity in sc abdominal adipose tissue when becoming obese. This might at least in part explain why men are more prone to accumulate fat in the abdominal region than are women.

The observation that lipolysis per cell differed between obese men and women, but not between lean subjects of either sex, further suggests that obesity influences lipolysis differently in males and females. A lower maximal lipolytic capacity in sc abdominal adipocytes in obese vs. lean subjects has previously been reported The previous study 10 , in contrast to the present, was conducted on a mixed population of both men and women.

Furthermore, the controls in the present study [as opposed to the previous one 10 ] had no family history of obesity. It has been shown that family history of obesity influences lipolysis in lean subjects Data from basal lipolysis were somewhat different from those from stimulated lipolysis.

It should be noted that the meaning of basal lipolysis measured in vitro is unclear, as fat cells in vivo always are exposed to regulatory hormones. However, the fact that basal lipolysis in obese women was elevated when expressed per cell and per cell surface area may suggest that it is not influenced by fat cell size.

It should be stressed that our findings may only relate to sc abdominal fat. Important regional differences in lipolysis within sc adipose tissue and between this region and the visceral one have been reported 6 , 7.

For ethical reasons it is not possible to investigate visceral fat in this type of study. In previous in vitro studies of lipolysis regulation after weight reduction, obese patients have usually been investigated after short-term and moderate weight loss has been achieved.

Conflicting results showing unchanged 12 , 14 , 15 , enhanced 13 , 16 , 25 , 28 , or reduced 29 catecholamine-induced lipolysis 12 , 13 — 16 , 25 , 28 , 29 after weight loss have been reported. Some effects may also be related to the diet itself rather than to weight loss.

Our findings were similar when subjects were investigated 2 yr after bariatric surgery, when there was a dramatic weight reduction, and 1 yr thereafter, when the additional weight loss was very small. This indicates that the findings were not secondary to decreased caloric intake, but, rather, to weight loss per se.

In an attempt to find the mechanisms responsible for the lipolytic capacity results we examined the protein content of HSL. As similar results were obtained with isoprenaline acting on β-adrenoceptors , forskolin acting on adenylyl cyclase , and Bu 2 cAMP acting on PKA , it is likely that our findings relate to events at or near HSL.

In both obese men and women, the adipose amount of HSL was markedly decreased, confirming data on mixed obese populations Furthermore, the amount of HSL protein was influenced by weight reduction.

In men it was slightly decreased. In women, however, no significant change was observed. It is clear that when HSL and lipolysis data are combined it is not possible to explain the gender variation on the basis of total amount of HSL protein.

There are, though, a number of other possible explanations for the gender difference related to HSL, such as phosphorylation status and translocation of the enzyme. Unfortunately, other mechanistical events could not be explained because of the lack of tissue.

Furthermore, the roles of as yet unidentified lipases other than HSL 30 remain to be established. In conclusion, in obesity the lipolytic capacity of abdominal sc fat cells is increased in women due to secondary factors, but is not changed in men.

This might be of importance for the difference in body fat distribution between obese men and women. The skillful technical assistance of Britt-Marie Leijonhufvud, Catharina Hertel, Eva Sjölin, and Kerstin Wåhlén is appreciated.

This work was supported by grants from the Swedish Medical Research Council, the Swedish Diabetes Association, the Juvenile Diabetes Foundation, the Wallenberg Foundation, the Swedish Heart and Lung Foundation, Karolinska Institute, King Gustav V and Queen Victoria Foundation, the Belvén Foundation, the Bergvall Foundation, the Novo Nordisk Foundation, the AMF Research Fund, the Swedish Society of Medicine, and the Foundation of Thuring.

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PubMed Google Scholar. Am J Clin Nutr — CAS PubMed Google Scholar. Pareek G, Hedican SP, Lee FT Jr, Nakada SY Shock wave lithotripsy success determined by skin-to-stone distance on computed tomography. Urology — Pareek G, Armenakas NA, Panagopoulos G, Bruno JJ, Fracchia JA Extracorporeal shock wave lithotripsy success based on body mass index and Hounsfield units.

Download references. Brian Eisner is a speaker for Boston Scientific Corporation and a consultant for the Ravine Group and PercSys. Marshall Stoller is a consultant for the Ravine Group and PercSys.

Matthew Cooperberg is a consultant for Abbott. All other authors have no disclosures. Department of Urology, GRB , Massachusetts General Hospital, 55 Fruit Street, Boston, MA, , USA.

Department of Urology, University of California-San Francisco, San Francisco, CA, USA. Javaad Zargooshi, Aaron D. Berger, Matthew R. Cooperberg, Sean M. You can also search for this author in PubMed Google Scholar. Correspondence to Brian H. Reprints and permissions. Eisner, B. et al. Gender differences in subcutaneous and perirenal fat distribution.

Surg Radiol Anat 32 , — Download citation. Received : 05 May Accepted : 24 June Published : 04 July Issue Date : November Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative. Abstract Purpose Body mass index BMI has been shown to influence the outcome of various surgical procedures. Methods A retrospective review was performed for patients who underwent radical or partial nephrectomy.

Results Mean anterior subcutaneous fat was significantly greater in females than in males 2. Conclusions Women exceed men in subcutaneous fat, while men exceed women in perirenal fat.

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