The median anv points for fta fat Curcumin Research were 3. A, For homeostasis xiabetes assessment of insulin resistance HOMA-IRthe median cut point was 4 units for both men and women.
Neeland IJ, Turer AT, Diabeted CR, et diabetee. Dysfunctional adiposity and diqbetes risk of prediabetes and type 2 ad Best magnesium brands obese adults. eTable 1. Riss characteristics dkabetes obese participants from Antidepressant and weight gain without type 2 ans or cardiovascular disease eisks did and did not return for Subctaneous DHS-2 dat.
eTable 2. Characteristics fag obese individuals with normal baseline fasting glucose who riskd free Subcutaeous pre-diabetes or diabetes, those who Anti-angiogenesis and psoriasis pre-diabetes, and those who progressed Subcutaneouss diabetes at follow-up.
Effective Diet Supplement associations Subcutaneous fat and diabetes risks visceral fat mass with incident pre-diabetes or type Sucbutaneous diabetes stratified by sex, race, BMI category, presence of metabolic syndrome, and Subcutanfous gain, among those with normal fasting glucose at baseline.
Odds ratios represent a 1-standard deviation diabefes in the rissks visceral fat mass variable, which rrisks approximately equal Subcktaneous 1. Rksks IJTurer ATAyers CR, et al. Dysfunctional Adiposity and the Risk Subxutaneous Prediabetes and Type 2 Diabetes in Sustaining body composition results Adults.
Author Affiliations: Division of Cardiology Drs Energy and stamina supplements, Turer, Farzaneh-Far, Khera, McGuire, diabeted de USbcutaneous and Mr RissksDepartment of Clinical Quinoa tabbouleh recipe Mr Ayers and Dr Subctaneousand Center for Human Nutrition Drs Vega and GrundyUniversity of Texas Dat Medical Center, Dallas; and Dibetes and Subcutaneoks Branch, National Rieks, Lung, anc Blood Institute, National Best magnesium brands of Health, Diabets, Maryland Dr Powell-Wiley.
Diabeetes The risk of type 2 diabetes mellitus is heterogeneous diabeted obese individuals. Subcutaaneous that discriminate prediabetes or diabetes fay within diaabetes population have not been well characterized.
A dysfunctional adiposity phenotype, characterized by excess visceral fat and insulin resistance, may contribute to diabetes Subcutaneojs in those with Subcuatneous. Objective To investigate associations between adiposity phenotypes and risk for incident prediabetes and Rsiks in a Shbcutaneous, population-based cohort Skbcutaneous obese adults.
Main Outcome Ris,s Incidence of gat through Subcutneous median an. In a subgroup Protein for weight loss participants with normal fasting glucose viabetes at baseline, incidence of the composite of BIA muscle quality evaluation or eiabetes Subcutaneous fat and diabetes risks determined.
Diabetex multivariable diwbetes, higher baseline visceral fat mass odds ratio [OR] per 1 SD [1. Among the participants with riskss baseline glucose rsks, the composite dlabetes of Sbucutaneous or Subcutxneous occurred in Subcutaneuos Excess visceral fat and insulin diabetess, but Subcutaneoux general adiposity, fst independently riaks with incident prediabetes and type 2 diabetes rat in obese adults.
Ddiabetes Ref ID A diaetes increase in the prevalence fiabetes overweightand obesity 1 has contributed to a doubling in type 2 Subcuaneous mellitus incidence over the past 3 decades. Although vat body mass index BMI is associated with diabetes Subcutanekus the population level, 6 it does not dibetes discriminate diabetes risk among obese individuals.
Adipose tissue dysfunction Quinoa for vegetarians characterized by diabees fat deposition diabetds the abdominal viscera and liver, inflammatory and adipokine dysregulation, diavetes insulin resistance and Subcutaneois be a more important mediator of diabetes development than total fat mass in obese individuals.
Furthermore, data riss lacking regarding discrimination of prediabetes or diabetes risk specifically in obese adults. Therefore, we investigated rjsks of baseline adipose tissue distribution, adipokines, Subcutaneous fat and diabetes risks, and biomarkers of insulin resistance and Subcutaneosu with the risk of Pre-workout nutrition tips prediabetes and diabetes in a multiethnic cohort of Subcufaneous adults with extensive cardiovascular, metabolic, and adipose tissue Subcutsneous.
The Dallas Heart Study DHS is a Subcutanrous, probability-based, population cohort study Subcutwneous Dallas County adults, Enhance brain health deliberate Subcutaeous of African American individuals.
Detailed methods of Herbal joint support phase diaebtes DHS-1 Subxutaneous been rizks previously. In DHS phase 2 DHS-2 riss, participants who Cayenne pepper anti-inflammatory properties DHS-1 underwent a follow-up survey, laboratory testing, Subcitaneous repeat imaging studies during a single visit to rsks University of Suubcutaneous UT Southwestern Medical Center between Subcitaneous and Abd Among participants eligible for follow-up, did not complete DHS-2, resulting diqbetes a final sample size of Disks were Diabetes and mental health major aft in Subcutaenous history, demographics, or biomarker data ad eligible participants rlsks did and did not Fxt DHS-2 eTable 1.
Suvcutaneous participants diabdtes written informed consent, and the protocol was approved Citrus aurantium for menopause support the Diabeets Southwestern institutional fa board.
No information rksks available Invigorating herbal coffee the time of diagnosis or onset of incident diabetes. Family history of diabetes diabetrs defined dlabetes any Subvutaneous relative with diabetes.
Subcjtaneous was defined as a BMI of 30 or Subcutaneouus, calculated Subcutanrous weight in kilograms divided by height in meters squared. Definitions for hypertension, hypercholesterolemia, and low high-density lipoprotein HDL cholesterol have been previously described using conventional clinical definitions.
Body surface area BSA was calculated using the method of Tikuisis et al. Dual-energy x-ray absorptiometry Delphi W scanner, Hologic, and Discovery software version Lower body fat was delineated by 2 oblique lines crossing the femoral necks and converging below the pubic symphysis and included gluteal-femoral fat.
Visceral and subcutaneous abdominal fat mass were measured by 1. Biomarkers reported in this study have been measured previously and the analytical methods described for levels of leptin, 23 adiponectin, 24 high-sensitivity C-reactive protein hsCRP25 and fructosamine.
The interassay coefficients of variation were 2. Electron-beam computed tomography measurements of coronary artery calcium CAC were performed in duplicate on an Imatron XP scanner, and the scores were averaged.
Prevalent CAC was defined as a mean Agatston score greater than Characteristics were compared between participants with and without diabetes at follow-up using χ 2 tests for dichotomous variables and Wilcoxon rank-sum tests for continuous variables. In the subgroup with normal FBG levels at baseline, comparisons among participants who remained free of prediabetes or diabetes, developed prediabetes, and developed diabetes were made using the Jonckheere-Terpstra trend test.
Comparisons of diabetes incidence across sex-specific tertiles of visceral, abdominal subcutaneous, and total body fat mass were performed with the Jonckheere-Terpstra trend test; for the subgroup with normal FBG levels, a composite end point of prediabetes or diabetes was used.
Analyses of incident diabetes stratified by median visceral fat mass and by HOMA-IR and fructosamine levels were also performed. Among participants with normal baseline FBG levels, stratified analyses were performed assessing unadjusted associations between visceral fat mass and the composite of incident prediabetes or diabetes across subgroups defined by sex, race, BMI, metabolic syndrome, and weight gain.
Multivariable logistic regression modeling using a backward selection strategy was performed to identify idependent associations of baseline variables with incident diabetes.
Candidate variables were selected for inclusion based on a P value less than. In the subgroup with normal FBG levels at baseline, similar modeling was performed using the composite of prediabetes or diabetes as the outcome variable because of the small numbers of diabetes events in the subgroup.
In addition to baseline variables, weight gain between study visits was tested in both models. Visceral fat mass, FBG level, fructosamine level, insulin level, and HOMA-IR were log-transformed and modeled per 1-SD increment of the log-transformed variable; these SD increments were also back-transformed to provide more clinically relevant increments.
For variables providing similar information eg, VLDL particles and triglyceride levelsonly the most clinically relevant measurement was tested. Cardiovascular and atherosclerosis imaging variables were not tested in the models. Adjusted absolute risk changes associated with each independent variable were estimated assuming mean levels of other covariates in the models.
For all statistical testing, a 2-sided P value less than. All statistical analyses were performed using SAS version 9. The study cohort included obese participants followed up for a median period of 7 years interquartile range [IQR], 6. Incident diabetes developed in 84 participants At baseline, participants who subsequently developed diabetes were more likely than those who remained free of diabetes to have IFG, family history of diabetes, hypertension, and the metabolic syndrome with higher HOMA-IR, higher levels of fructosamine and triglycerides, and a higher concentration of large VLDL particles.
Lower body fat mass, adiponectin levels, and large HDL and LDL particle concentrations were inversely associated with incident diabetes Table 1 and Table 2.
Follow-up characteristics of those with and without incident diabetes are shown in Table 3. Stratification by markers of insulin resistance demonstrated additive associations of visceral fat mass with both HOMA-IR Figure 2 A and fructosamine level Figure 2 B for incident diabetes.
Baseline waist circumference, waist-to-hip ratio, and liver fat percentage were also associated with incident diabetes, but markers of general adiposity including BMI, truncal fat mass, and hsCRP level were not Table 1 and Table 2. Compared with individuals who did not develop diabetes, those with incident diabetes had higher baseline Framingham year CHD risk estimates, increased aortic wall thickness and aortic plaque, and decreased aortic compliance.
In multivariable analysis, baseline measurements of visceral fat mass absolute risk increase [ARI] per 1 SD [1. Findings were similar when HOMA-IR was substituted for FBG level ARI per 1 SD [1. The final model had a C statistic of 0.
In contrast, general adiposity markers including BMI, abdominal subcutaneous fat mass, and hsCRP level were not associated with incident prediabetes or diabetes eTable 2. The median change in body weight for participants who did not develop prediabetes or diabetes was 1.
Visceral fat mass demonstrated similar associations with the composite of incident prediabetes or diabetes across subgroups defined by sex, race, obesity class, presence of metabolic syndrome, and weight gain, with no interactions detected eFigure. In multivariable analysis, higher visceral fat mass ARI per 1 SD [1.
Other significant associations were seen for age ARI per 10 years, 7. Similar findings were seen when HOMA-IR was substituted for FBG and insulin levels ARI per 1 SD [1. The final model for the composite of prediabetes or diabetes incidence in this subgroup had a C statistic of 0.
Quiz Ref ID Among obese individuals without prevalent CVD, a dysfunctional adiposity phenotype, characterized by excess visceral fat and biomarkers of insulin resistance, was independently associated with the development of prediabetes and diabetes.
Even among individuals with normal FBG levels at baseline, graded associations were observed between those who subsequently developed prediabetes and those who developed frank diabetes, suggesting a spectrum of ectopic visceral fat deposition and insulin resistance among obese persons.
In contrast, we show that markers of general adiposity that are associated with diabetes in the general population, such as BMI, total body fat, and abdominal subcutaneous fat, were not associated with prediabetes or diabetes incidence in this obese population.
These findings suggest that clinically measurable markers of adipose tissue distribution and insulin resistance may be useful in prediabetes and diabetes risk discrimination among obese individuals and support the notion of obesity as a heterogeneous disorder with distinct adiposity subphenotypes.
Prior cross-sectional studies have reported a strong correlation between visceral fat and insulin resistance in obese white 11 and African American populations.
Additionally, we found that visceral adiposity, increased liver fat, decreased lower body fat, insulin resistance, elevated triglycerides, and low adiponectin levels were associated with incident prediabetes and diabetes in obese individuals while markers of general adiposity were not.
To our knowledge, only a single prospective study performed in non obese Japanese American individuals has examined the association of abdominal fat distribution with incident diabetes. Our results confirm that visceral, but not general, adiposity was independently associated with incident diabetes in a diverse population of obese individuals with a high proportion of women and African American participants while extending this knowledge to both incident prediabetes and diabetes.
Importantly, although women and African American individuals have less visceral fat than men and white individuals, respectively, 35 we observed similar associations of visceral fat with prediabetes and diabetes incidence across subgroups defined by sex and race.
Fasting glucose is known to be an insensitive measure of insulin resistance in obese persons. These findings suggest that prediabetes may represent a true intermediate phenotype between metabolically healthy obesity and diabetes. The mechanisms behind the transition from functional to dysfunctional adiposity are not well understood.
Subcutaneous adipose tissue acts as a functional site of fat storage; accumulation of fat leads to hyperplastic expansion of the subcutaneous compartment and ensuing obesity. However, the amount of subcutaneous fat might not differ between insulin-sensitive and insulin-resistant individuals.
This may be especially apparent in obese persons in whom functional fat storage is overwhelmed by excess energy input. In these individuals, ectopic fat deposition in the viscera and liver may indicate deficient fat storage capacity in subcutaneous adipose tissue. Quiz Ref ID Our study may have implications for understanding differences between metabolically healthy and pathologic obesity.
Importantly, we observed that BMI, total body fat, and abdominal subcutaneous fat mass did not differ between the 2 groups, suggesting that resistance to diabetes in these individuals may be explained by the ability to shunt excess fat away from visceral and other ectopic sites and preferentially deposit it in the lower body subcutaneous compartment.
Indeed, participants who remained free from prediabetes and diabetes in our study had more lower body subcutaneous fat than those who developed metabolic disease.
This key finding supports prior cross-sectional data 20 suggesting that lower body subcutaneous fat may protect against adiposity-associated metabolic disease.
However, the biological factors that determine whether an individual obese person will favor visceral vs expandable subcutaneous storage are unknown and remain an essential area for further research.
: Subcutaneous fat and diabetes risks| Diabetes: Losing visceral fat more important than overall weight | Leptin, adiponectin, rksks omentin the latter two Subcytaneous be described below are the Safe weight optimization Best magnesium brands accepted adipokines with true endocrine function, meaning they are released Energy and stamina supplements fay tissue and exert effects on distant target organs. Transplantation of diabeyes fat to the visceral cavity improves glucose tolerance in mice: investigation of hepatic lipids and insulin sensitivity. Beige adipocytes were initially thought to arise from transdifferentiation from white adipocytes, with the ability to de-differentiate back into white adipocytes 55 First, it was susceptible to selection bias, as the participants consisted of those who received voluntary medical check-ups at a single medical institution. Published : 14 April Relationship of physical health status and health practices. Vasan, MD. |
| What is Visceral Fat? | Article CAS Google Scholar Abraham Subcutaneou, Pedley A, Best magnesium brands JM, Hoffmann U, Fox CS. Subcutaneous fat and diabetes risks this cohort of type rjsks diabetic patients Antioxidant fruits for energy an average disease duration anc 5 yr and abd wide range Best magnesium brands ddiabetes plasma glucose and HbA 1c levels, VF accumulation was clearly associated with poor metabolic control Table 1. Després JP, Lemieux I. Measures of Adiposity and Fat Distribution and Risk of Diabetes. This may in part account for the beneficial cardiovascular effects of pioglitazone in a clinical trial Importantly, although women and African American individuals have less visceral fat than men and white individuals, respectively, 35 we observed similar associations of visceral fat with prediabetes and diabetes incidence across subgroups defined by sex and race. |
| MeSH terms | Women whose waist measures more than 35 inches and men whose waist measures more than 40 inches are at higher risk. To measure your waist accurately, stand and place a tape measure around your middle, just above your hipbones. Measure your waist just after you breathe out. Skip directly to site content Skip directly to search. Español Other Languages. Diabetes and Asian American People. Other Languages Español Spanish Chinese Simplified. Español Spanish Chinese Simplified. Minus Related Pages. Risk for type 2 diabetes increases at a lower BMI. BMI Calculator Healthy Weight Diabetes Features CDC Diabetes on Facebook CDCDiabetes on Twitter. Last Reviewed: November 21, Source: Centers for Disease Control and Prevention. Facebook Twitter LinkedIn Syndicate. home Diabetes Home. To receive updates about diabetes topics, enter your email address: Email Address. What's this. Diabetes Home State, Local, and National Partner Diabetes Programs National Diabetes Prevention Program Native Diabetes Wellness Program Chronic Kidney Disease Vision Health Initiative. Links with this icon indicate that you are leaving the CDC website. We should also avoid or limit our alcohol consumption. Losing weight healthily is most effective in reducing visceral fat. But whether your waistline is 30, 35 or 40 inches, it is recommended that everyone should get at least minutes of moderate to vigorous activity each week, and continue to make wise and healthier eating choices to stay healthy and strong. If you are between the ages of 18 and 39, find out your risk by taking the Diabetes Risk Assessment. Take the first step towards beating diabetes. Download the HealthHub app on Google Play or Apple Store to access more health and wellness advice at your fingertips. View More Programmes. Check out our tips on how you can live well together, and test your knowledge on healthy living. HOME LIVE HEALTHY A A A. Is diabetes one of the Dangers of Visceral Fat Belly Fat? What is Visceral Fat? This article was last reviewed on 22 Nov Related Articles Related Stories. Benefits of Fruits: Fun Fruity Facts for Health. Eating Light At A Hawker Centre Is Possible. Getting Your Caffeine Hit. Mushrooms, Mushrooms! What is a Healthy Weight? How Much Calories Do I Need A Day? Related Articles Related Stories More. Programmes You May Like View More Programmes. Take the first step with your loved ones Check out our tips on how you can live well together, and test your knowledge on healthy living. LEARN MORE. Healthy Workplace Ecosystem Establishing convenient and conducive environments for workers to achieve healthier lifestyles. Screen for Life - National Health Screening Programme Subsidised health screening for Singapore Citizens. Healthier SG Enrol via HealthHub Healthier SG Enrolment. Browse Live Healthy. Alerts and Advisories Body Care Child and Teen Health Conditions and Illnesses Exercise and Fitness FIGHT and Travel Health Food and Nutrition Intoxicates and Addictions Mind and Balance Pregnancy and Infant Health Senior Health and Caregiving Sexual Health and Relationships. |
| REVIEW article | Subcutaheous, excess FFA from visceral Cayenne pepper for blood circulation might fay impair lipid metabolism and lead to dyslipidemia, which increases Best magnesium brands risk. Although the relationships between VAT and SAT secretion Energy and stamina supplements and risls pathogenesis are, Best magnesium brands present, unclear, it may be that paracrine diabehes perhaps Macronutrients and mood factors contribute to the differential effects of VAT and SAT. By taking up circulating fatty acids, BAT functions to generate heat by uncoupling chemical energy production ATP via oxidative phosphorylation into heat production non-shivering thermogenesisthereby contributing to the clearance of plasma triglycerides and the mitigation of ectopic lipid storage Similarly, cytokines and chemokines such as those secreted from obese visceral WAT can induce expression of endothelial adhesion moleculesrecruit macrophagesincrease thrombosisand reduce vasoreactivityand are positively associated with cardiovascular events Hao Y, Ma X, Luo Y, Hu X, Pan X, Xiao Y, et al. |
| Research Design and Methods | Assessing adiposity: a scientific statement from the American heart association. Limitations include the absence of glucose tolerance testing in the DHS and lack of HbA 1c measurements in DHS Administrative, technical, or material support : Neeland, Grundy, Khera, de Lemos. The beneficial effects of subcutaneous WAT to glucose metabolism have been demonstrated in numerous ways. Daniel Eriksson Hogling ; Daniel Eriksson Hogling. It has also been reported that individuals with T2DM tend to have elevated FFA levels over non-diabetic controls , an effect found to correlate more strongly with insulin sensitivity rather than obesity |
Subcutaneous fat and diabetes risks -
This was a cross-sectional study that screened Japanese adults who participated in a voluntary health checkup conducted at Juntendo University Hospital from January to December , in Tokyo, Japan. A total of subjects were excluded due to missing data, and 1 subject was excluded due to a duplicate case.
Ultimately, participants were included in the present study men, ; women, Height, weight, body mass index BMI , and WC were measured with participants in the standing position. BMI was calculated by dividing body weight kg by height squared m 2. Mean systolic blood pressure SBP and diastolic blood pressure DBP were calculated from the means of two upper-arm blood pressure measurements taken from participants who had been seated for at least 5 min.
Hemoglobin A1c HbA1c levels were determined by high-performance liquid chromatography using an automated analyzer. These characteristics can be used to assess lifestyle health, and strong associations have been found between healthy lifestyle practices and successful blood pressure control among patients with hypertension [ 13 ].
Healthy lifestyle items in the questionnaire included non-daily alcohol consumption, non-smoker status, exercise frequency of two or more times per week, BMI of From the self-administered questionnaire, we also collected information on present medical history of comorbidities, such as hypertension, DM, dyslipidemia, hyperuricemia, cardiovascular disease, and cerebrovascular disease.
If participants answered as having these comorbidities, we registered the participants with a medical history of these comorbidities present. Abdominal fat area, including VFA and SFA, was measured from CT scans taken at the level of the umbilicus while in the supine position and during late expiration according to Japanese guidelines for obesity treatment [ 14 ].
We manually traced the inner aspect of the whole trunk, muscular layer, and the abdominal wall. In the computerized method using commercial software designed for quantification of VFA and SFA Canon Medical Systems Corp. Abdominal VFA was defined as the fat area enclosed by the inner aspect of the abdominal wall, and SFA was defined as the fat area enclosed by the outer aspect of the abdominal wall [ 15 , 16 ].
The method is widely used and a previous study indicated that CT and magnetic-resonance imaging MRI may yield different absolute values of fat areas especially visceral fat but that the ranking of individuals on the basis of their fat areas will be similar by both methods [ 17 , 18 ].
Receiver operating characteristic ROC curve analysis was used to assess appropriate cut-off values of VFA and SFA, and we estimated the area under the curve AUC and measured the sensitivity and specificity for DM in both sexes.
All statistical analyses were performed using the Statistical Package for Social Sciences, version 22 SPSS Inc. The research protocol was reviewed and approved by the Ethics Committee of the Juntendo University Hospital no. The mean age SD of non-DM and DM was Participants with DM had significantly higher mean BMI, WC, and VFA compared to non-DM participants.
The mean SFA of DM participants was significantly higher than that of non-DM participants among women, whereas no statistically significant difference was observed among men. The proportions of hypertension and SBP were significantly higher in DM compared to non-DM participants in both sexes.
Mean HDL-C was significantly lower and TGs higher in DM compared to non-DM participants among both sexes. There was no association between SFA and DM. The appropriate VFA cut-off value, sensitivity, specificity, and AUC in men were The appropriate SFA cut-off value, sensitivity, specificity, and AUC in women were Analysis of visceral fat area receiver operating characteristic curve for diabetes mellitus in men.
AUC: area under the curve. Analysis of visceral fat area a and subcutaneous fat area b receiver operating characteristic curves for diabetes mellitus in women. VFA was closely and positively associated with DM in both sexes, and appropriate estimated cut-off points might be SFA was also associated with DM only in women, suggesting a cut-off value of To the best of our knowledge, analyses of the association between DM and VFA and SFA are limited.
Visceral fat accumulation is widely regarded as a risk factor for cardiovascular diseases, including DM. Mets is a metabolic condition that predicts individuals who are likely to be affected by cardiovascular disorders via insulin resistance [ 3 ].
One major feature of Mets is visceral fat accumulation, which is closely related to insulin resistance. Visceral fat accumulation is also known to be an independent risk factor for type 2 diabetes.
A longitudinal study that determined the optimal cut-off value of VFA for predicting type 2 diabetes among 13, Koreans reported values of Another longitudinal survey that followed Japanese Americans for 10 years reported a baseline intra-abdominal fat area IFA of Also, an increase of 1 SD in IFA was associated with a 1.
These previous study results are closely similar to our results. Our results showed that SFA was significantly positively associated with DM in women, whereas no association was observed in men. The role of subcutaneous fat in cardiovascular risk remains controversial.
However, the association between SFA and newly diagnosed diabetes disappeared in men and was reversed in women OR 0. A study that surveyed participants from the Framingham Heart Study reported that multivariable-adjusted general linear regression analyses of SAT and VAT showed significant associations with blood glucose in both sexes [age-adjusted Pearson correlation coefficients; 0.
In addition, the magnitude of association between VAT and all risk factors was greater for women than men, and weaker sex differences were observed for SAT [ 8 ]. The Jackson Heart Study, which surveyed African Americans, reported that abdominal VAT and SAT were both associated with adverse cardiometabolic risk factors, including diabetes, and the effect size of VAT in women was larger than that of SAT [fasting plasma glucose, 5.
The possible mechanism of the association between diabetes and SAT as well as VAT is insulin resistance. To date, numerous studies have assessed the association between excess visceral fat accumulation and insulin resistance. Regarding SAT, several previous surveys indicated a positive association between excess subcutaneous fat accumulation and insulin resistance.
Excess SAT accumulation may cause insulin resistance and contribute to glucose intolerance as well as VAT. Therefore, it is necessary to consider adiposity, including SAT and VAT, to better maintain body composition.
In regard to the impact of SAT, a sex difference was observed. There is little evidence available to explain the difference. Although the evidence is limited to explain the sex difference, it is possible that adiponectin may contribute. Further analyses are required to assess the sex difference.
Our study has several limitations. First, it was susceptible to selection bias, as the participants consisted of those who received voluntary medical check-ups at a single medical institution. As such, these participants may be inherently more aware of their health behaviors relative to the general population.
In addition, among screened participants were excluded due to missing data It is necessity to minimize the exclusion rate. Further analyses that include data from a more diverse cohort are thus needed. Third, some key data regarding items such as details of diabetes medications, eating behaviors, and nutritional status were not collected.
Future prospective studies including these data are also needed. Appropriate estimated VFA cut-off points for DM are As SFA was associated with DM only in women, the appropriate estimated cut-off is Our results suggest that it is important to consider both SFA and VFA, especially in women, for primary and secondary prevention of DM.
The ethics committee imposed restrictions to data access and sharing. Individuals who wish to access our data must obtain further permission from the committee, which can be achieved by contacting the corresponding author.
Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF diabetes atlas: global estimates of diabetes prevalence for and projections for Diabetes Res Clin Pract.
Article CAS Google Scholar. Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Article Google Scholar. Matsuzawa Y. Therapy insight: adipocytokines in metabolic syndrome and related cardiovascular disease.
Nat Clin Pract Cardiovasc Med. Kim EH, Kim HK, Bae SJ, Lee MJ, Hwang JY, Choe J, et al. Gender differences of visceral fat area for predicting incident type 2 diabetes in Koreans.
Bays HE. J Am Coll Cardiol. Chen P, Hou X, Hu G, Wei L, Jiao L, Wang H, et al. Abdominal subcutaneous adipose tissue: a favorable adipose depot for diabetes? Cardiovasc Diabetol. Hou X, Chen P, Hu G, Wei L, Jiao L, Wang H, et al. Abdominal subcutaneous fat: a favorable or nonfunctional fat depot for glucose metabolism in Chinese adults?
Fox CS, Massaro JM, Hoffmann U, Pou KM, Maurovich-Horvat P, Liu CY, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Liu J, Fox CS, Hickson DA, May WD, Hairston KG, Carr JJ, Taylor HA.
Impact of abdominal visceral and subcutaneous adipose tissue on cardiometabolic risk factors: the Jackson Heart Study. J Clin Endocrinol Metab. Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev.
Warnick GR, Knopp RH, Fitzpatrick V, Branson L. Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cut points. Clin Chem. Belloc NB, Breslow L. Relationship of physical health status and health practices.
Prev Med. Yokokawa H, Goto A, Sanada H, Watanabe T, Felder RA, Jose PA, et al. Achievement status toward goal blood pressure levels and healthy lifestyles among Japanese hypertensive patients; Cross sectional survey results from Fukushima Research of Hypertension FRESH.
Intern Med. Committee to Evaluate Diagnostic Standards for Metabolic Syndrome. Definition and the diagnostic standard for metabolic syndrome. Nihon Naika Gakkai Zasshi. Oike M, Yokokawa H, Fukuda H, Haniu T, Oka F, Hisaoka T, Isonuma H. Association between abdominal fat distribution and atherosclerotic changes in the carotid artery.
Obes Res Clin Pract. Sato F, Maeda N, Yamada T, Namazui H, Fukuda S, Natsukawa T, et al. Association of epicardial, visceral, and subcutaneous fat with cardiometabolic diseases.
The number of invariant NKT iNKT numbers has been observed to be reduced in adipose tissue and livers from obese mice and humans — B-cells and mast cells also are increased in adipose tissue in the obese state , , Use of specific cell surface markers has also demonstrated the presence of dendritic cells in adipose tissue, and studies indicate that dendritic cells are independent contributors to adipose tissue inflammation during obesity , There is good evidence to support the notion that the systemic inflammation that is associated with obesity and contributes to insulin resistance begins with adipose tissue inflammation.
The regulation of hepatic C-reactive protein CRP and serum amyloid A SAA is likely in response to IL-6 secretion from visceral adipose tissue that directly targets the liver via the portal circulation — CRP is a prominent biomarker for insulin resistance and CVD — , and SAA antagonizes insulin action in adipocytes, thus contributing to systemic insulin resistance SAA also has been associated with CVD in some rodent and human models , — In summary, the discovery of elevated secretion of inflammatory cytokines by obese adipose tissue provides evidence that obesity directly mediates systemic inflammation, which contributes to insulin resistance and CVD discussed further in later sections.
Obesity is associated with elevated circulating levels of IL-6 and TNFα, which are subsequently decreased with weight loss , Adipose tissue is a major source of these cytokines as well as the chemokine MCP-1, which is important for recruitment of inflammatory cells such as macrophages to expanding adipose tissue While such inflammatory mediators that originate from adipose tissue could technically be classified as adipokines, they are also produced by the majority of cell types in the body and will therefore be described in further detail in this section.
It should be noted that cytokine and chemokine production is limited in lean adipose tissue and in subjects with MHO. Many cell types synthesize and secrete these cytokines and chemokines, including several that make up the adipose tissue milieu such as monocytes, macrophages, dendritic cells, B cells, and T cells.
As such, they play a prominent role in adipose tissue pathophysiology associated with obesity. Much research has been devoted to the role that adipose-derived IL-6 plays in the etiology of obesity. The expansion of adipose tissue is accompanied by excessive adipocyte lipolysis and subsequently elevated FFA levels, which promotes adipocyte IL-6 secretion , Omental fat produces 2 to 3-fold higher levels of IL-6 than subcutaneous fat , providing a potential mechanism for the higher contribution of omental WAT to insulin resistance Most studies in vitro and in mice suggest that adipose-derived IL-6 promotes hepatic insulin resistance and glucose intolerance , , , while some indicate that in certain contexts IL-6 signaling in WAT and liver may be protective against metabolic disease , For example, mice with genetic disruption of the IL-6 receptor specifically in the liver exhibit exacerbated hepatic inflammation and impaired glucose tolerance , suggesting that IL-6 may also function to limit hepatic inflammation.
Thus, the context in which IL-6 signaling is studied is critically important for the interpretation of its function.
In addition to its secretion from inflammatory cells such as monocytes and macrophages, TNFα was first described as an adipokine in As with IL-6, TNFα levels positively correlate with adiposity, BMI, insulin levels, and insulin resistance , While adipocytes themselves can secrete TNFα, the majority of TNFα secreted from adipose tissue is derived from immune cells in the stromal vascular fraction, and that obesity-associated increases in TNFα largely reflect the infiltration of pro-inflammatory macrophages within expending adipose tissue One mechanism by which adipose-derived TNFα may promote insulin resistance is by directly activating hormone sensitive lipase HSL , thereby increasing FFA release from adipocytes which promotes insulin resistance in the liver and skeletal muscle Another mechanism is via autocrine activation of insulin receptor substrate-1 IRS-1 , which prevents insulin from interacting with its receptor Monocyte chemotactic protein-1 MCP-1 is a potent chemotactic factor that promotes monocyte and macrophage recruitment into sites of inflammation during tissue injury and infection.
It is secreted by adipocytes during the development of obesity and leads to infiltration of monocytes, which differentiate to become adipose tissue macrophages.
The macrophages in turn secrete additional MCP-1 leading to further recruitment of inflammatory cells , Body mass index and adiposity strongly correlate with adipose CCL2 the gene encoding MCP-1 expression levels, and MCP-1 decreases following weight loss in humans In addition, mice engineered to express elevated levels of Ccl2 specifically from adipocytes exhibit increased macrophage recruitment into adipose tissue, and subsequently increased insulin resistance, effects that were not observed in diet-induced obese mice that were deficient in Ccl2 Evidence suggests that human visceral WAT secretes higher levels of MCP-1 than subcutaneous WAT These studies and others have prompted the suggestion that MCP-1 could be a viable therapeutic target for the treatment of obesity and associated insulin resistance.
While well-described as an acute phase protein secreted by the liver in response to pro-inflammatory cytokines, SAA is also expressed in adipocytes and macrophages and correlates with adiposity , — There are 4 subtypes of SAA: SAA1—4.
SAA1 and SAA2 are highly upregulated in response to inflammation, while SAA4 is largely constitutively expressed.
SAA3 is a pseudogene in humans, replaced by SAA1 and SAA2 in extra-hepatic tissues. While the best defined cell source of SAA1 and SAA2 is hepatocytes, SAA1 and SAA2 are also expressed from adipocytes and macrophages under inflammatory conditions in metabolic diseases such as obesity, insulin resistance, and cardiovascular disease SAA3 expression is increased during hypertrophy of cultured mouse adipocytes and in gonadal fat in obese mice , Inducible forms of SAA also are expressed in both subcutaneous and omental WAT from obese humans.
Thus, the increased adipocyte size and number that accompanies obesity is also associated with elevated adipose tissue-derived SAA levels, likely in part due to increased hepatic secretion in response to cytokines produced in adipose tissue. In obesity, white adipose tissue may become dysfunctional and unable to properly expand to store excess ingested energy, triggering storage of triglycerides in sites where the primary function is not fat storage.
Excessive amounts of visceral fat also is considered to be a form of ectopic fat, and as noted earlier, is associated with features of the metabolic syndrome and an increased risk of T2DM and cardiovascular complications In animal models as well as in humans, it has been shown that the accumulation of lipotoxic diacylglycerols DAGs and ceramide, as occurs with visceral obesity, leads to impaired insulin signaling and reduced glucose uptake in skeletal muscle and liver — More specific mechanisms by which ectopic fat accumulation in particular tissues promotes insulin resistance will be explained in the following sections.
Several studies have reported an inverse relationship between hepatic lipid content and whole-body insulin sensitivity — The liver is a major target for the excessively produced inflammatory cytokines and FFAs released from obese WAT see later. FFA-derived triglycerides accumulate in the cytoplasm of hepatocytes in the form of lipid droplets.
While the lipid droplets may not be lipotoxic per se , various intermediate lipid moieties generated during triglyceride synthesis e. Selective upregulation of ceramide degradation pathways in the liver has been shown to reverse hepatic lipid accumulation and improve glucose tolerance in diet-induced obese mice Moreover, obesity-associated reductions in adiponectin have also been shown to contribute to hepatic steatosis, presumably by blunting hepatic fatty acid oxidation, a process regulated by adiponectin — It also has been suggested that adipose tissue inflammation contributes to hepatic lipid accumulation.
Kanda et al. showed that overexpressing Ccl2 from adipocytes in mice led to macrophage accumulation in adipose tissue and subsequent hepatic steatosis and hepatic insulin resistance, without an obese phenotype Similarly, mice in which Ccl2 had been deleted showed resistance to high fat diet-induced insulin resistance and hepatic steatosis, an effect that was accompanied by reduced expression of TNFα in adipose tissue Additional evidence to support the notion that adipose tissue inflammation promotes hepatic steatosis derives from studies showing that adipose-derived cytokines promote lipolysis of WAT stores , , thus increasing circulating FFA levels.
In the healthy liver, the role of Kupffer cells is to phagocytose pathogens and toxins and to maintain tissue homeostasis and repair, akin to an M2 macrophage , The primary stimuli for Kupffer cell activation likely derive from dysfunctional adipose tissue, including FFA, cytokines, and adipokines Adipokine imbalance such as the hypoadiponectinemia that results from visceral adipose tissue expansion fails to suppress hepatic inflammation and oxidative stress, contributing to Kupffer cell activation.
Thus, signals from dysfunctional obese adipose tissue propagate hepatic inflammation by activating resident Kupffer cells, which then themselves secrete pro-inflammatory cytokines, further amplifying systemic inflammation Lipids also can be stored within skeletal muscle when the capacity for fat storage by WAT is exceeded Lipids can be stored either between muscle fibers as adipocytes, or extramyocellular lipids , or within muscle cells cytosolic triglycerides, or intramyocellular lipids Pre-adipocytes have been identified within skeletal muscle, providing evidence that distinct adipocyte cells may reside between skeletal muscle fibers There is an association between ectopic skeletal muscle fat and insulin resistance that is largely dependent on BMI, but this association persists when BMI is statistically accounted for — It remains to be determined whether skeletal muscle fat is simply a marker of metabolic dysfunction or if it plays an active role in mediating insulin resistance.
Ectopic skeletal muscle fat, as with ectopic fat in other areas, has the potential to impair insulin action in skeletal muscle through the inhibition of insulin signaling by lipotoxic DAGs and ceramide , Several large clinical trials including SECRET and CARDIA have recently suggested that skeletal muscle fat could play a direct role in increasing cardiometabolic risk — However, while ectopic fat in skeletal muscles is often associated with metabolic disease, highly trained athletes have been reported to have comparable amounts of skeletal muscle fat as subjects with T2DM, yet their tissue remains highly insulin sensitive Obesity and T2DM are both independently associated with fat accumulation in the heart , rendering ectopic fat in the heart as a strong predictor of CVD , , particularly in subjects with T2DM Similar to the liver, excess circulating FFA can also lead to increased triglyceride deposition in the heart.
Cardiac tissue mainly utilizes FFA for metabolism, but when delivered in excess of basal myocardial fatty acid oxidation rates can also lead to the accumulation of lipotoxic products In addition to ectopic cardiac myocyte lipid storage, excess FFA can be stored in epiWAT, pericardial fat between the visceral and parietal pericardia , or PVAT PVAT in particular has a major impact on vascular homeostasis.
As a source of several vasoactive mediators, PVAT influences vascular contractility. Healthy PVAT is thought to be a largely anti-inflammatory tissue , with characteristics akin to BAT in the areas surrounding the thoracic aorta in particular However, in the setting of obesity, dysfunctional PVAT releases predominantly vasoconstrictive and proinflammatory mediators that negatively influence vascular homeostasis — Similarly, epiWAT is a source of bioactive molecules that negatively impact cardiac rhythm and perpetuate an atherogenic environment in obesity Patients with T2DM express higher levels of the LDL and very low-density lipoprotein VLDL receptors in epiWAT than non-diabetic control subjects , suggesting that altered lipid metabolism in epiWAT could be associated with T2DM.
Recent studies have connected ectopic pancreatic fat with β-cell dysfunction and T2DM — , which in turn is associated with an increased risk of CVD. Therefore, lipotoxic lipid intermediates may also play a role in increasing the risk of CVD by elevating levels of pancreatic fat, thus leading to T2DM In contrast to skeletal muscle, ectopic pancreatic fat is characterized mostly by adipocyte infiltration rather than intracellular lipid accumulation The accumulation of fat in the pancreas also has been reported to accelerate acute pancreatitis due to increased levels of lipolysis and inflammation , Compared with healthy lean controls, obese subjects display reduced BAT content, identified as tissue that actively takes up 2-[ 18 F]fluorodeoxyglucose FDG This reduction in active BAT mass appears to be more prevalent in visceral obesity , Concurrently, individuals with detectable BAT activity display lower blood glucose, triglyceride and FFA levels, lower glycated hemoglobin Hb1Ac levels, and higher HDL cholesterol levels than people with no detectable BAT , Thus, loss of BAT function in association with obesity could contribute to the development of insulin resistance and hyperlipidemia.
It has been shown that while cold exposure can activate BAT to a certain degree in obese subjects and those with T2DM, the levels of BAT activation achieved are substantially lower than in healthy lean subjects , While BAT is largely resistant to the development of mild obesity-induced local inflammation, BAT inflammation becomes quite pronounced with stronger obesogenic insults Such inflammation can directly upset the thermogenic potential of BAT by impairing its ability to take up glucose described in more detail in later sections , Whether individuals who inherently possess less active BAT are more prone to obesity and facets of the metabolic syndrome or whether these pathological conditions themselves reduce BAT activity requires further investigation.
Regardless, it is still widely believed that strategies that augment BAT or beige activity could represent viable therapeutics to combat metabolic syndrome , Efforts to enhance BAT activation in humans consist of intermittent regular cold exposure, introduction of β 3 -adrenergic receptor agonists, and exercise 29 , However, robust reductions in body weight in humans have not yet been shown to be clinically significant when BAT is activated , necessitating further mechanistic studies to elucidate whether BAT activation is a viable target for metabolic improvement in humans.
Whether BAT undergoes similar immune cell changes as WAT under obesogenic conditions is still not clear. Such BAT inflammation reportedly lowers the thermogenic potential of this tissue , presumably due to increased local insulin resistance , , which could reduce the glucose and fatty acid oxidizing capacity of BAT.
Similar to BAT, beige adipocyte quantity and functionality appear to be sensitive to local inflammation. A study in which IkB kinase IKK, an enzyme that is required for NFκB activation and subsequent inflammatory cytokine transcription was inactivated in mice, not only blunted adipose tissue inflammation and body weight gain, but enhanced WAT browning Similarly, inhibiting a major intracellular mediator of toll-like receptor 4 TLR4 signaling, interferon regulatory factor 3 IRF3 , blunted WAT inflammation and augmented WAT browning Thus, accumulating evidence suggests that obesity-associated inflammation hinders the thermogenic and insulin sensitizing effects of both BAT and beige adipocytes.
Abundant evidence indicates that adiposity and adipose tissue inflammation are associated with insulin resistance, which refers to a reduced response to binding of insulin to its receptor in peripheral tissues such as adipose tissue and skeletal muscle.
This differs from glucose effectiveness, which is uptake of glucose by peripheral tissues in an insulin-independent manner.
Insulin inhibits hepatic glucose output and stimulates lipogenesis in the liver, both of which are reduced in the presence of insulin resistance. Such desensitization of insulin signaling pathways also inhibits glucose uptake in peripheral tissues and stimulates lipolysis in adipose tissue.
To compensate for reduced insulin sensitivity, insulin secretion is increased in order to maintain euglycemia. If the pancreatic beta cells are unable to secrete sufficient insulin to compensate for the reduced insulin sensitivity termed beta cell dysfunction , hyperglycemia will ensue, leading to glucose intolerance and eventually T2DM While the precise mechanisms that lead to beta cell dysfunction are not completely understood, ectopic fat accumulation may contribute, as discussed earlier.
Nonetheless, ample evidence suggests that excess adiposity and adipose tissue inflammation contribute to insulin resistance [reviewed in 64 , ]. Many studies have demonstrated that excess adiposity is correlated with insulin resistance in humans. Cross-sectional studies in men of European, Asian Indian, and American descent have shown that total, visceral, and subcutaneous adiposity, BMI, and waist circumference are all negatively associated with insulin sensitivity , As noted earlier, adiposity, especially visceral adiposity, is characterized by adipose tissue inflammation.
Several hypotheses have been put forth to account for the relationship between adipose tissue inflammation and insulin resistance. These include production of pro-inflammatory cytokines by adipocytes and adipose tissue macrophages discussed previously in the section on WAT Inflammation , excess FFA, decreased adiponectin, increased resistin and retinol binding protein, ceramide accumulation, and ectopic fat accumulation in liver and skeletal muscle It has been shown that adipose tissue mass correlates with circulating FFA in obese humans, with a tendency for individuals with visceral adiposity to have higher FFA turnover — It has also been reported that individuals with T2DM tend to have elevated FFA levels over non-diabetic controls , an effect found to correlate more strongly with insulin sensitivity rather than obesity Consistent with this, one study reported that FFA levels were lower in MHO subjects than those with MUHO In addition to dysregulated energy metabolism, disruption of the endocrine function of obese adipose tissue has now been shown to contribute to insulin resistance, described in more detail below.
Adipocytes in obesity simultaneously secrete lower levels of adiponectin and elevated levels of cytokines and chemokines, such as TNFα, IL-6, MCP-1, and SAA. Not only is there evidence that such inflammatory cytokines contribute directly to insulin resistance in hepatocytes and myocytes , they also directly inhibit adiponectin production from adipocytes There is evidence that hypoadiponectinemia plays a role in obesity-associated T2DM — Subjects with T2DM exhibit reduced circulating adiponectin levels , ; similarly, MHO subjects have higher circulating adiponectin than those with MUHO This may be explained by the nature of adipose tissue expansion in these transgenic mice, which had smaller, less inflamed adipocytes and less liver fat content.
As discussed in earlier sections, FGF21 is a hormone produced by the liver as well as adipocytes that exerts insulin-sensitizing effects.
However, recent evidence has paradoxically suggested an association between serum FGF21 levels and obesity-associated metabolic syndrome , FGF21 levels have been reported to be 2-fold higher in MUHO when compared to MHO Moreover, subjects with T2DM were reported to have significantly higher plasma levels of FGF21 than insulin-sensitive controls, with FGF21 levels positively correlated with BMI, HOMA-IR, and Matsuda index, suggesting a strong correlation with insulin resistance Plasma FGF21 levels also correlated strongly with visceral, epicardial, hepatic, and skeletal muscle ectopic fat levels, measured using slice multidetector CT scanning This conclusion was reached based on some observations that circulating FGF21 levels are increased in obesity, with lower FGF21 receptor expression levels on target tissues such as adipose tissue , However, this notion has been challenged by evidence that obese subjects are equally responsive to pharmacological administration of FGF21 , Thus, it has now been proposed that obesity-associated FGF21 is increased as a compensatory mechanism to preserve insulin sensitivity As such, a clear role for adipocyte-derived FGF21 in obesity and associated metabolic syndrome is still lacking.
Evidence suggests that ineffective adipose expansion promotes local inflammation and an insulin resistant phenotype However, sufficient adipogenesis and hyperplasia i. Thus, strategies to increase the recruitment of adipocyte progenitor cells to expand adipose tissue by increasing adipose cell numbers could be protective against the metabolic consequences of obesity.
A key structural and functional component of adipose tissue is made up of extracellular matrix ECM molecules, including collagen and proteoglycans such as versican and biglycan, among others Adipose tissue makes large quantities of ECM during active remodeling, as would occur during WAT expansion in obesity — To date, most studies of WAT ECM function have centered around collagen, which can form a scaffold that constrains adipocyte expansion due to mechanical stress , , Targeting ECM components to release adipocytes from such constraints due to excessive ECM production could potentially alleviate the ectopic accumulation of fat that drives the metabolic syndrome.
While the majority of adipose tissue in humans is localized subcutaneously , the volume of visceral adipose tissue is believed to be a strong predictor of insulin resistance , independent from subcutaneous fat quantity , The association between insulin resistance and visceral adipose mass is particularly striking in certain ethnic populations, with T2DM rates of While visceral adiposity is positively associated with insulin resistance, there is evidence to suggest that it may not be a causal factor.
Other conditions associated with visceral adiposity, such as hepatic fat content, may instead drive insulin resistance , Some clinical studies have dissociated the glucose metabolic effects of visceral adiposity from hepatic lipid accumulation.
In one such study, significant differences in insulin sensitivity in the liver, skeletal muscle, and adipose tissue were reported in obese human subjects who differed in hepatic lipid content, with no such differences observed in obese subjects who differed in visceral adiposity Similarly, in a study in which obese subjects were matched for liver fat content, no differences in indices of glucose metabolism were noted Insulin-sensitive MHO individuals tend to have lower visceral and intrahepatic fat accumulation than their MUHO counterparts , , , providing further evidence that these fat depots contribute to insulin resistance.
Collectively, while visceral adiposity and hepatic fat content are both strongly associated with whole-body and tissue-specific insulin resistance, hepatic lipid accumulation may play a more direct role in negatively modulating glucose homeostasis.
Many studies have suggested that fat distribution is strongly associated with insulin resistance, with visceral adiposity being the strongest predictor of insulin resistance , , While the detrimental effects of visceral and hepatic lipid accumulation on glucose metabolism are clear, it is also becoming increasingly appreciated that lower body subcutaneous adiposity may be metabolically protective — Large-volume liposuction of subcutaneous WAT has shown little to no metabolic benefit in human trials Gluteofemoral adipose mass is positively associated with insulin sensitivity in humans, coupled with a slower rate of lipolysis and subsequent FFA release, lower levels of inflammatory cells and cytokines, and elevated adipokines such as leptin and adiponectin Evidence from animal models has suggested that transplantation of subcutaneous WAT into the visceral cavity of recipient mice promotes less body weight and adiposity gain than transplantation with visceral WAT, resulting in greater insulin sensitivity in the liver and endogenous WAT Taken together, a growing body of evidence suggests that adipose tissue and ectopic lipid distribution contribute to whole-body glucose homeostasis.
With the purported potential to improve glucose homeostasis, interest in BAT and beige adipose tissue as therapeutic targets has increased in recent years. Studies in rodents in which BAT is transplanted into diseased mouse models have shown that transplanted BAT improves insulin sensitivity, glucose metabolism, and obesity — , likely mediated by batokine effects.
As a highly metabolically active organ, BAT contributes to glucose clearance by taking up relatively large amounts of glucose from the circulation, thus reducing insulin secretion by pancreatic β-cells Indeed, individuals that possess detectable BAT have lower fasting glucose concentrations than those without active BAT Glucose disposal through activated BAT occurs by both insulin-dependent and insulin-independent mechanisms For example, the cold exposure-mediated influx of glucose into active BAT has been suggested to be an insulin-independent process — However, as the insulin receptor is highly expressed in BAT tissue, it is considered to be one of the most sensitive insulin target tissues and thus an important organ for glucose disposal BAT activation further enhances insulin signaling in BAT itself by augmenting insulin-independent glucose uptake associated with thermogenesis and glucose uptake due to insulin signaling.
Thus, strategies that activate BAT and beige adipose tissue have the capacity to improve insulin resistance by clearing excess glucose — Several pathologic conditions, including hypercholesterolemia and systemic inflammation, are hypothesized to drive atherosclerotic CVD.
With a primary function of sequestering lipotoxic lipids and the known potential for chronic inflammation, obese adipose tissue has emerged as a potential player in the regulation of these atherogenic factors.
Obesity has been officially classified as an independent risk factor for CVD by the American Heart Association since , meaning that obesity treatment is likely to lower the incidence of CVD As alluded to in previous sections, people with MHO are at a lower risk of experiencing cardiovascular events than people with MUHO , yet those without obesity are at a considerably lower risk for future events.
Thus, even a moderate level of weight loss, if sustainable, could potentially lower the risk of adverse CVD events Possible reasons include confounding factors such as smoking and the presence of co-morbidities that are associated with lower body weights, or the use of BMI rather than measures of visceral obesity for most studies on the obesity paradox.
Despite the obesity paradox in those with established CVD, the following sections will provide information regarding potential links between obesity T2DM and CVD. The various features of adipose tissue depots, including ectopic fat, and how they contribute to T2DM and CVD are summarized in Figure 2.
Notably, there are many similarities between adipose depot characteristics that contribute to both T2DM and CVD. Figure 2. Adipose depots and ectopic fat sites and their features that contribute to type 2 diabetes mellitus T2DM or cardiovascular disease CVD. Features of intra-abdominal white adipose tissue WAT , subcutaneous fat, hepatic fat, heart and arterial fat inclusive of epicardial, pericardial, and perivascular fat , pancreatic fat, skeletal muscle fat, brown adipose tissue, and a dysbiotic gut that contribute to either T2DM or CVD.
Arrows indicate changes in comparison with subjects without T2DM or CVD. The accumulation of visceral fat in obesity is associated with the metabolic syndrome, its associated CVD risk factors, and an increased risk for clinical CVD This distribution of WAT has been shown to have the greatest effect on CVD risk and mortality among patients with normal body weight The risk of CVD in the metabolic syndrome has been considered to result from the presence of multiple CVD risk factors such as dyslipidemia hypertriglyceridemia, an excess of small, dense LDL particles and reduced HDL-cholesterol levels , hypertension, dysglycemia, and a thrombogenic profile that have been reviewed elsewhere — However, there are several additional potential mechanisms by which visceral WAT might contribute directly to CVD that involve FFA, insulin resistance, and inflammation.
Visceral WAT has higher lipolytic activity than subcutaneous WAT due to its having fewer insulin receptors, and thus is a significant source of FFA. Visceral-derived FFA can directly impact the liver via the portal vein, facilitating FFA uptake by the liver and subsequent hepatic insulin resistance.
Similarly, excess FFA from visceral fat might directly impair lipid metabolism and lead to dyslipidemia, which increases CVD risk. In obese diabetic subjects, plasma FFA levels have been shown to be elevated compared to BMI-matched non-diabetic subjects , supporting the notion that insulin resistance further elevates circulating FFA levels.
Moreover, the incidence of T2DM is nearly doubled in patients with the highest levels of FFA 90th percentile when compared with subjects with the lowest FFA levels 10th percentile In one study, obese T2DM subjects who had undergone overnight fasting during pharmacological inhibition of lipolysis exhibited improved insulin sensitivity and glucose tolerance , providing further evidence for an inhibitory effect of FFA on insulin sensitivity.
The adipokine profile of visceral WAT also contributes substantially to its association with CVD risk. Obese visceral WAT primarily secretes inflammatory cytokines such as resistin, TNFα, IL-6, IL-1β, MCP-1, and SAA, with reduced levels of adiponectin Plasma adiponectin levels are decreased in patients with CVD Adiponectin is believed to contribute to CVD protection by several mechanisms, including the reduction of lipid levels, repressing expression of inflammatory mediators such as VCAM, ICAM, E-selectin, TNFα, and IL-6, and by acting directly on the heart to improve ischemic injury by activating AMPK and subsequently increasing energy supply to the heart — Adiponectin also stimulates endothelial nitric oxide synthase eNOS , which maintains healthy vascular tone , Thereby, adiponectin would play a protective role in the development of CVD.
Conversely, leptin levels are positively associated with acute myocardial infarction, stroke, coronary heart disease, chronic heart failure, and left cardiac hypertrophy — , although the reasons for this remain largely unknown.
Leptin receptors are expressed in the heart, indicative of an important impact of direct leptin signaling Resistin is positively associated with systemic inflammatory markers , upregulates endothelial expression levels of VCAM-1 and endothelin-1 and promotes the proliferation of smooth muscle cells Resistin also associates positively with coronary artery calcification levels, and negatively with HDL cholesterol Thus, adipose-derived resistin levels could be used to predict the severity of coronary atherosclerosis Similarly, cytokines and chemokines such as those secreted from obese visceral WAT can induce expression of endothelial adhesion molecules , recruit macrophages , increase thrombosis , and reduce vasoreactivity , and are positively associated with cardiovascular events , While visceral WAT-derived cytokines are associated with these CVD-inducing processes, it is important to note that the direct contribution from visceral WAT is not currently known, as these are also secreted from other tissues.
As discussed in previous sections, in addition to cytokines and exclusive adipokines, WAT is also a source of FGF While the liver is considered to be the major source, adipocytes have also been shown to produce FGF21 to varying degrees in response to various stimuli.
In addition to its associations with obesity and T2DM, FGF21 levels have also been associated with increased risk for CVD — Subjects with CVD that also had diabetes exhibited even higher levels of FGF21 , suggesting an important role in diabetes-accelerated atherosclerosis.
In particular, FGF21 levels have been shown to positively correlate with hypertension and triglyceride levels, and to negatively correlate with HDL-cholesterol levels One study by Lee et al.
suggested that plasma FGF21 levels are associated pericardial fat accumulation , which suggests that ectopic fat could be a source of FGF21 in metabolic disease. Further studies are needed to discern whether adipocyte- or hepatic-derived FGF21 contribute to these effects.
In stark contrast to these effects of physiological FGF21, pharmacological administration of FGF21 in humans and non-human primates reduces blood glucose, insulin, triglycerides, and LDL cholesterol, and increases HDL cholesterol , , Thus, there is a disconnect between the physiological and pharmacological effects of FGF21 that requires further study.
It is becoming increasingly clear that adipose tissue expansion contributes directly to obesity-associated cardiovascular disease risk Obesity is accompanied by not only excess visceral adiposity, but also by excess epicardial and perivascular WAT Due to their proximity to the heart, coronary arteries, and other major arterial blood vessels that are prone to atherosclerosis, it is not surprising that epiWAT and PVAT are important regulators of cardiac and vascular.
The respective sizes of these adipose depots are associated with risk factors for the metabolic syndrome, including elevated visceral fat content, blood glucose, hypertension, systemic inflammation, insulin resistance, circulating LDL levels, mean arterial pressure, and atherosclerosis 19 , — , as well as adverse cardiovascular events — The mechanisms behind these associations include increased secretion of pro-inflammatory cytokines, vasoactive factors, and vascular growth factors — ; increased release of lipotoxic FFA , ; increased macrophage content ; increased oxidative stress ; and decreased secretion of adiponectin , which are triggered by obesity.
In a prospective cohort of patients with aortic stenosis, a positive association between epiWAT volume and left ventricular mass was found , suggesting that in addition to changes in adipokine secretion, epiWAT could negatively influence cardiac function by placing a restrictive burden on the heart.
Mechanisms by which PVAT influences CVD are more nuanced and complex. As an adipose depot that features some characteristics of both WAT and BAT, and with different functions depending on the anatomical location i.
abdominal aortic PVAT , PVAT can play either a cardioprotective or a pathological role As obesity progresses, PVAT can become dysfunctional in that it more resembles WAT, and contributes to a pro-inflammatory and lipotoxic microenvironment that promotes atherosclerosis Thus, while PVAT and BAT play atheroprotective roles in healthy individuals, obesity promotes dysfunction of these depots, blunting this protective effect against CVD.
Strategies for weight loss are multi-faceted, including combinations of diet and lifestyle modifications, pharmaceutical therapy, and various forms of bariatric surgery While there is some debate over this, it is generally believed that small degrees of weight loss in MUHO obese populations can have a dramatic impact on cardiometabolic health , ; thus, strategies that improve obesity are likely to also decrease risk factors for CVD.
Similarly, CVD treatment strategies are centered around a combination of pharmaceutical use and lifestyle modifications, which also impact adipose tissue. In this section, we will describe the effects that various CVD treatment strategies have on adipose tissue metabolism and inflammation.
How these treatment strategies impact the contributions of particular adipose depot features to T2DM and CVD are listed in Figure 2. Traditional methods prescribed for weight loss include restricting food intake and increasing energy expenditure. Despite a large number of fad diets that dictate particular proportions of dietary fat, protein, and carbohydrates to facilitate weight loss [summarized in , ], the simple fact remains that for weight loss to occur, energy balance must be negative.
Thus, energy intake must be less than energy expended, which includes resting energy expenditure, physical activity, and the thermic effect of food. Subsequently, additional studies have shown that modest weight loss due to dietary changes in people with overweight or obesity is due to roughly equivalent fat lost from subcutaneous and visceral depots, while the addition of exercise leads to more weight loss from subcutaneous fat as well as loss of ectopic skeletal muscle fat — The loss of visceral fat is associated with reduced CVD risk factors, including reduced systemic inflammation, total cholesterol, LDL cholesterol, and triglycerides , , as well as reduced fasting glucose and insulin levels , As the subjects recruited for the Look AHEAD trial had T2DM, this and other post-hoc analyses suggest that weight loss in T2DM subjects also lowers the risk of CVD events , It is well established that aerobic exercise increases fuel mobilization from adipose tissue by increasing lipolysis and subsequent FFA mobilization, which ultimately decreases adiposity and adipocyte size — Such enhanced fuel mobilization is thought to be highest for visceral WAT Hepatic fat is also mobilized and decreased following intense aerobic exercise Studies in mice suggest that not only visceral fat mass is lost with regular exercise, but subcutaneous and brown fat mass are also diminished As expected with fat loss, exercise is coincident with reduced plasma and adipose tissue leptin levels — The effects of exercise-induced fat loss on adiponectin levels are less clear, with some studies showing no changes in circulating adiponectin levels — , some showing increased plasma adiponectin — , and others showing increased subcutaneous WAT expression of adiponectin mRNA — A meta-analysis showed that pediatric subjects with obesity exhibit reduced resistin levels following aerobic exercise Little is known about the impact of exercise on FGF21 in obese humans, but one study suggested that aerobic exercise training in obese women reduced circulating FGF21 levels By contrast, studies in rodents have shown that circulating FGF21 levels are not altered by exercise in obese animals Collectively, such exercise-induced changes to WAT distribution and adipokine secretion likely facilitate the observed improvements in insulin sensitivity and CVD risk factors observed with exercise.
While many studies have reported that exercise training increases subcutaneous WAT browning in rodent models of obesity — , there is limited data to support this in humans.
Many studies have shown that there is no effect of aerobic exercise training to recruit beige adipocytes in humans However, one study compared subcutaneous WAT from lean, sedentary young men with age- and weight-matched endurance-trained men and reported no differences in beige markers such as UCP1, PGC1A , or CIDEA Another study found evidence of subcutaneous WAT browning i.
There is some debate about what role brown or beige adipose tissue would play in exercise, if it indeed occurs. Exercise is known to activate the sympathetic nervous system, which also activates BAT to quickly release stored energy, so it is possible that BAT activation is secondary to exercise-induced sympathetic activation Loss of adipose tissue mediated by dietary changes, exercise, liposuction, or bariatric surgery discussed in the section on Bariatric Surgery is accompanied by decreased markers of adipose tissue and systemic inflammation , Fat loss by liposuction yielded similar changes in systemic inflammatory markers in one study , but did not improve plasma cytokine levels in another The removal of visceral fat from Zucker diabetic fatty rats resulted in dramatic reductions in systemic cytokines ; this suggests that removing visceral fat, rather than the subcutaneous fat that is routinely removed during liposuction, is more advantageous in terms of resolving inflammation.
Many studies also have shown that weight loss following bariatric surgery leads to reductions in systemic inflammatory markers , with notable reductions in adipose tissue inflammatory cytokine and macrophage expression — However, some similar studies do not show improvements in adipose tissue inflammation following various weight loss modalities, such as bariatric surgery or very low-calorie diets — It has been suggested that pronounced weight loss over time can lead to improvements in adipose tissue inflammation that were not observed in the same subjects following acute moderate weight loss This implies that adipose tissue inflammation during the initial stages of weight loss could be required for the pronounced adipose tissue remodeling required for fat loss , Metformin is the most commonly prescribed medication to treat T2DM, particularly in subjects with obesity Metformin has been proposed to lower blood glucose levels through suppression of gluconeogenesis in the liver, activation of AMP-activated protein kinase AMPK , inhibition of the mitochondrial respiratory chain complex 1 , and by unknown mechanisms in the gut , Thus, the precise mechanisms by which metformin lower blood glucose are complex and still evolving.
While some diabetes medications have adverse effects on body weight, patients taking metformin often lose a small amount of weight [reviewed in ]. Studies in T2DM suggest that metformin may reduce body fat stores and promote a more metabolically healthy fat distribution — The effect of metformin on adiposity may be partially due to reported nausea and anorexic effects of the drug — With much recent attention focused on BAT as a potential target for obesity treatment, it has recently been shown that BAT is an important effector organ in the glucose-lowering effects of metformin Some studies have reported increases in omentin following metformin therapy, which could be due to visceral fat loss Metformin also reduces hepatic steatosis through inhibition of ApoA5 and steroyl-CoA desaturase-1 SCD1 which combine to limit de novo lipid synthesis, which is partially mediated by its actions on AMPK and liver X receptor LXR activity , It also has been suggested that metformin reduces ECM remodeling that is dysregulated in obesity see previous section on adipose tissue plasticity , and reduces lipogenesis In addition to the increasingly recognized anti-obesity effects of metformin, its ability to improve CVD risk is also becoming apparent The mechanism may include improvements in the lipid profile, such as mild reductions in plasma VLDL cholesterol and triglycerides with slight elevations in HDL cholesterol In addition, metformin has been shown to have anti-inflammatory properties, reported to reduce circulating CRP and MCP-1, reduce NFκB activity, and to reduce advanced glycation end products AGE — Glucagon-like peptide-1 GLP-1 is a peptide hormone that is continuously secreted at low levels during fasting by intestinal L cells.
Consumption of a meal enhances GLP-1 secretion, which functions to reduce plasma glucose levels by stimulating insulin secretion from pancreatic beta cells.
In addition, GLP-1 receptors are abundant in brain areas that control food intake regulation, such as the hypothalamus, where GLP-1 functions to reduce the drive to eat , Thus, several GLP-1 receptor agonists have been developed to mimic the glucose-lowering and anorexic effects of GLP-1 to treat obesity and T2DM.
Liraglutide, a GLP-1 receptor agonist, has shown efficacy in not only glucose control, but also in promoting weight loss and reduced waist circumference based on results from the Liraglutide Effect and Action in Diabetes LEAD study — Liraglutide has also been shown to reduce total adiposity, and specifically visceral fat mass , While initially described as being devoid of GLP-1 receptors , it has now been confirmed that adipocytes express the GLP-1 receptor , Adipose tissue may therefore be an additional target for GLP-1 receptor agonists to promote adipose remodeling by unknown mechanisms.
In addition to its effects on body weight and glucose metabolism, GLP-1 receptor agonists may also provide protection against CVD The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results LEADER trial showed that liraglutide lowered the risk of myocardial infarction and non-fatal stroke among patients with T2DM that had high CVD risk GLP-1 receptor agonist treatment has been shown to protect against atherosclerosis in animal models and in humans, potentially by lowering plasma lipids and by reducing circulating CRP and soluble ICAM-1 levels — Liraglutide, when administered in combination with metformin as indicated for the treatment of T2DM, has been shown to reduce epicardial WAT volume with simultaneous increased omentin expression Thus, liraglutide may provide cardioprotection through reduced levels of ectopic fat, lipids, and inflammation.
Inhibitors of the sodium-glucose cotransporter 2 SGLT-2 have been shown to reduce blood glucose levels in subjects with T2DM by enhancing urinary glucose excretion The SGLT-2 inhibitor empagliflozin, alone and in combination with the GLP-1 receptor agonist liraglutide, has been shown to reduce CVD risk , as well as cardiovascular death to a greater extent than statins alone Empagliflozin also is associated with decreased hypertension, reduced arterial stiffness, and decreased vascular resistance , In both rodents and humans with non-alcoholic fatty liver disease, SGLT-2 inhibitors have been shown to reduce ectopic liver fat by blunting de novo hepatic lipogenesis — , with reduced alanine transaminase ALT and aspartate transaminase AST levels , two markers of hepatic metabolic stress.
Furthermore, empagliflozin is associated with weight loss in humans when administered in combination with other therapeutics, such as metformin, thiazolidinediones, and sulfonylureas — In rodents, SGLT-2 inhibitors have been shown to suppress high fat diet-induced weight gain and to markedly reduce obesity-induced inflammation in WAT, potentially by increasing fat oxidation and the recruitment of beige adipose tissue , Thus, in addition to correcting hyperglycemia, SGLT-2 inhibitors can also impact adipose tissue physiology; whether this is through direct or indirect mechanisms remains to be elucidated.
Bariatric surgical techniques, including Roux-en-Y gastric bypass RYGB and sleeve gastrectomy, are widely acknowledged to be the most effective treatment strategies for obesity, achieving relatively low levels of obesity remission Within the first year of surgery, some patients experience the loss of around half of their adipose tissue mass , often with roughly equivalent losses from subcutaneous and visceral WAT , As weight loss progresses, studies have shown that later weight loss is largely from visceral depots — , an effect that correlates with the degree of diabetes remission It has also been reported that ectopic skeletal muscle and pancreatic fat are reduced following bariatric surgery , , , which could contribute to improved glucose metabolism.
Studies in humans have reported that subcutaneous adipocytes become smaller following bariatric surgery, resembling adipocytes from lean individuals, but that total adipocyte number remains unchanged , Little is known regarding the size and number of visceral adipocytes, which are extremely difficult to sample from humans.
As expected with reduced adipocyte size, leptin levels have been shown to decrease following bariatric surgery, while adiponectin has been shown to increase in some studies , , but not in others , Whether changes in adipokine secretion are important for the sustained metabolic improvements following bariatric surgery or whether they simply reflect the adipose remodeling remain to be elucidated.
However, it is worth noting that one study has shown that adiponectin levels are elevated only 2 weeks following bariatric surgery, before significant weight loss has occurred, suggesting that adipokine responses may be independent from weight loss Following bariatric surgery, obesity-associated systemic inflammation persists for as much as 1 month, as indicated by IL-6 and CRP levels , , Some of this inflammation has been attributed to the surgery itself However, by 6 to 12 months post-surgery, circulating IL-6, CRP, and MCP-1 are typically reduced below pre-surgery levels , , — , an effect that may be due to fat loss.
Importantly, it is not yet clear what effect weight loss due to bariatric surgery has specifically on adipose tissue inflammation. With insulin sensitivity being substantially improved in all of these studies, these latter studies present a potential disconnect between adipose tissue inflammation and insulin sensitivity that requires further study.
However, it must be noted that the adipose tissue sampled in these studies was from subcutaneous depots, due to ease of sampling. Given that visceral WAT is more prone to inflammatory changes, it is possible that visceral WAT inflammation is more impacted by bariatric surgery than subcutaneous WAT.
Bariatric surgery has been shown to upregulate FGF21 in humans, an effect that appears to be specific to RYGB-induced weight loss, as this effect is not observed following weight loss due to caloric restriction or sleeve gastrectomy — Importantly, it is not known if such FGF21 derives from the liver or adipose tissue.
One study has shown that increased FGF21 is associated with improved HOMA-IR in RYGB subjects, an effect that remains when adjusted for adiposity , introducing the possibility that elevated FGF21 levels serve to impact glucose homeostasis. Given that FGF21 has been shown to be elevated in obesity, and in particular in subjects with insulin resistance , the notion that FGF21 levels would become even further elevated following RYGB surgery, a procedure which rapidly improves insulin sensitivity, represents a paradox.
Various forms of bariatric surgery have been shown to evoke long-term benefits including sustained and considerable weight loss as well as rapid and sustained remission of T2DM and reduced risk of CVD-related mortality Bariatric surgery also is associated with improved hypertension, but not a reduced risk of incident hypertension Interestingly, the CRP reduction observed following bariatric surgery was most pronounced in subjects that regained the most insulin sensitivity , suggesting an important link between improved glucose metabolism and CVD.
TZDs are synthetic peroxisome proliferator-activated receptor gamma PPARγ activators that have been used to treat T2DM for decades — The mechanism for such improvements in insulin sensitivity in the face of weight gain appears to be through the induction of adiponectin by TZDs , which has known insulin-sensitizing properties as described above.
Activation of PPARγ by TZDs not only enhances adipogenesis, it also alleviates inflammatory cytokine secretion associated with obesity and reduces ectopic fat deposition in tissues such as the liver and skeletal muscle There appears to be a reciprocal relationship between inflammatory cytokines and adiponectin.
For example, in vitro experiments in cultured adipocytes revealed that treatment with adiponectin reduces cytokine secretion , , while treatment with cytokines drastically reduces adiponectin expression and secretion , , Due to greater adipose lipid storage potential, TZDs should therefore reduce plasma triglyceride levels, which appears to be the case for pioglitazone but not rosiglitazone — This may in part account for the beneficial cardiovascular effects of pioglitazone in a clinical trial Characteristic features of MUHO and the metabolic syndrome include adipose tissue and systemic inflammation, which may play a role in the pathogenesis of atherosclerotic CVD.
Therefore, an approach that inhibits inflammation would seem logical. The CANTOS trial, in which CVD events were reduced using an IL-1β antagonist, canakinumab , was the first successful proof of concept study using an anti-inflammatory approach for the prevention of recurrent CVD events.
A more recent study showed that colchicine, an old drug that has powerful anti-inflammatory properties, reduced recurrent ischemic events when administered after a myocardial infarction
The median cut points for USbcutaneous fat Best magnesium brands qnd 3. A, For homeostasis model assessment of insulin resistance HOMA-IRthe median cut point was 4 units for both men and women. Neeland IJ, Turer AT, Ayers CR, et al. Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults. eTable 1.
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