Thermogenesis and body composition -
Indeed, recent work comparing cold-tolerant Tibetan pigs to cold-sensitive Bama pigs has provided direct evidence of adaptive thermogenesis in subcutaneous sWAT and perirenal WAT Lin et al. Furthermore, morphological studies show that in response to cold exposure, subcutaneous adipose tissue displays evidence for beige cell recruitment with an increase in multilocular adipocytes, increased mitochondrial DNA copy number and increased expression of PGC1a and the beige cell marker CD Wu et al.
Furthermore, in Tibetan pigs cold tolerant , cold exposure increased the expression of the UCP3 gene and protein in isolated subcutaneous adipocytes and this is associated with increased uncoupled respiration, providing evidence to suggest an increase in UCP3-driven thermogenesis Lin et al.
Role of thermogenesis in determining cold tolerance in pigs. Tibetan pigs are cold tolerant and this coincides with the recruitment of beige adipocytes in subcutaneous WAT in response to cold exposure. Although pigs do not that express functional uncoupling protein UCP 1, adipocytes exhibit UCP3 and this mediates mitochondrial uncoupling and adipose tissue thermogenesis.
The contribution of UCP3 to brown fat thermogenesis has been contentious and appears to be dependent on the species studied. In mice, earlier work suggested that BAT thermogenesis was dependent on UCP1 Matthias et al.
Despite this, hamsters that lack functional UCP3 specifically in brown adipocytes have increased propensity to weight gain, which is indicative of a reduction in energy expenditure Fromme et al. Although innate differences in UCP3 expression in adipose tissue of pigs have been linked to cold tolerance, to date, there are no data on BAT-specific UCP3 function and the control of body weight in this species.
In addition to UCP3-associated uncoupling and thermogenesis, recent data suggest that SERCA-driven beige cell thermogenesis also occurs in pigs. Indeed, the work by Ikeda et al. Ikeda et al. Retroviral expression of PRDM in subcutaneous porcine adipocytes increases the expression of beige-cell-specific markers including CIDEA and TMEM26 Ikeda et al.
Furthermore, decreased SERCA2b expression reduced basal and noradrenaline-induced oxygen consumption and extracellular acidification rates in isolated pig adipocytes Ikeda et al.
Thus, it is now clear that adipose tissue thermogenesis and the associated energy expenditure are not solely mediated via UCP1 and mitochondrial uncoupling, but in fact, a number of cellular pathways, across both adipose tissue and skeletal muscle, act in concert to determine total thermogenic potential.
In lambs, the expression of UCP1 is maximal in perirenal adipose tissue on the first postnatal day, rapidly declining with the expansion of WAT Symonds , Pope et al. Mapping of UCP1 mRNA in lambs shows abundant expression in sternal and retroperitoneal adipose depots compared to omental fat, which is a predominantly WAT depot Symonds et al.
Indeed, adult sheep retain UCP1 expression in both sternal and retroperitoneal fat and this coincides with post-prandial heat production, albeit this response is greater in the sternal fat depot Henry et al.
This coincides with the expression of UCP1 protein, where UCP1-positive brown-like adipocytes were only detectable in sternal adipose tissue of adult ewes Henry et al. Data logger temperature probes have been employed to measure longitudinal heat production in multiple tissues to index thermogenic output in sheep.
Sheep are a grazing species and therefore do not display typical meal-associated excursions such as changes in ghrelin secretion. Despite this, temporal food restriction in sheep entrains a pre-prandial rise in ghrelin Sugino et al.
Furthermore, post-prandial thermogenesis in both skeletal muscle and retroperitoneal adipose depots is markedly enhanced by intracerebroventricular infusion of leptin Henry et al.
Thus, in spite of relatively low levels of UCP1 in adult sheep, skeletal muscle and specific adipose depots retain thermogenic capacity. Over recent years, we have utilised the sheep to dissect the differential roles of adipose tissue and skeletal muscle thermogenesis in the long-term control of body weight, which is discussed in detail in the following section.
Similar to other species, ovine body weight can be readily manipulated through dietary management Henry et al. Sheep are ruminants and thus body weight is increased through feeding a high-energy diet enriched in lupin grain and oats. Diet-induced obesity, however, is not associated with any change in heat production in adipose tissues or skeletal muscle of sheep Henry et al.
On the other hand, long-term food restriction and low body weight are associated with a homeostatic decrease in thermogenesis in sternal and retroperitoneal adipose tissue and skeletal muscle Henry et al.
Importantly, similar to humans, the reduction in thermogenesis caused by food restriction and low body weight is still evident at one year post-weight loss, which suggests that homeostatic changes in thermogenesis contribute to impaired weight loss and increased long-term weight regain Henry et al.
Effect of chronic food restriction and weight loss on adaptive thermogenesis in ewes. Tissue temperature recordings show that caloric restriction and low body weight cause a homeostatic decrease in night time thermogenesis in ovariectomised ewes.
This metabolic adaptation occurs in both sternal adipose tissue adipose tissue enriched in uncoupling protein 1 and skeletal muscle and to a lesser extent in retroperitoneal adipose tissue.
The reduction in thermogenesis is associated with increased expression of neuropeptide Y NPY in the arcuate nucleus and melanin-concentrating hormone MCH in the lateral hypothalamus. The homeostatic reduction in thermogenesis is coordinated by the hypothalamus.
Long-term weight loss in ovariectomised ewes increases the expression of the orexigenic neuropeptides NPY in the arcuate nucleus and melanin-concentrating hormone MCH in the lateral hypothalamus LH to increase hunger and reduce energy expenditure Henry et al.
Regarding the anorexigenic melanocortin pathway, the effect of low body weight on the expression of POMC is controversial with data showing a decrease Backholer et al.
This is not surprising since POMC is the precursor to multiple neuropeptides, only one of which includes aMSH and the ultimate end product is dependent on post-translational processing Mountjoy On the other hand, increased Agrp and Npy expression and reduced Pomc mRNA have been observed in rodents Bi et al.
Thus, weight-loss-induced changes in hypothalamic gene expression are likely to reduce thermogenesis, whilst causing a concurrent increase in hunger drive.
This represents a homeostatic mechanism to protect against weight loss and promote weight regain in calorie-restricted individuals. Animals were originally selected for innate differences in adiposity by measuring back fat thickness and two lines were created via selective breeding strategies.
A key feature of the genetically lean and obese sheep is an inherent difference in the growth hormone GH axis, where lean animals have increased mean GH concentration in plasma and an associated increase in pituitary gland weight Francis et al.
The increase in pituitary gland weight is primarily due to a greater number of cells in the lean animals Francis et al. Furthermore, expression of GH and the GH secretagogue receptor GHSR is greater in genetically lean sheep, indicating differential responses to ghrelin, an agonist of the GHSR French et al.
This suggests that innate differences in the set-point of the GH axis may underpin differences in adiposity in the genetically lean and obese sheep; however, this is only one aspect that could contribute to this phenotype.
Interestingly, food intake is similar in genetically lean and obese sheep as is the expression of POMC, Leptin Receptor and NPY in the arcuate nucleus.
On the other hand, lean animals have elevated post-prandial thermogenesis in retroperitoneal adipose tissue and this coincides with increased expression of UCP1 in this tissue Henry et al.
The divergence in thermogenesis is specific to adipose tissue since post-prandial thermogenesis is similar in genetically lean and obese animals Henry et al.
Despite similar expression of appetite-regulating peptides in the arcuate nucleus of the hypothalamus, genetically lean sheep have increased expression of MCH and pre-pro-orexin ORX in the LH compared to obese animals Anukulkitch et al. While both neuropeptides are considered orexigenic Shimada et al.
Deletion of MCH in mice results in hypophagia and a lean phenotype Shimada et al. Orexin is critical in the embryonic development of BAT in mice Sellayah et al. Thus, increased expression of ORX in the LH of lean sheep may be an important physiological determinant of increased thermogenesis in retroperitoneal fat and the associated changes in adiposity.
It is widely recognised that there is marked variation in the glucocorticoid response to stress or activation of the hypothalamo-pituitary adrenal HPA axis Cockrem , Walker et al.
The activity of the HPA axis in response to stress is impacted on by age Sapolsky et al. Nonetheless, in any given population individuals can be characterised as either high HR or low LR glucocorticoid responders Epel et al. It is important to note that female LR and HR sheep have similar basal plasma cortisol concentration and divergence in glucocorticoid secretion only occurs in response to ACTH or stress Lee et al.
Previous studies have suggested that obesity itself causes perturbation of the HPA axis with impaired glucocorticoid-negative feedback Jessop et al. Furthermore, cortisol directly impacts on metabolic function; however, this will not be addressed in the current review.
Initial studies in rams show that high cortisol response to adrenocorticotropin ACTH is associated with lower feed-conversion efficiency Knott et al.
Furthermore, in rams, adiposity is correlated to cortisol responses to ACTH Knott et al. More recent work shows that identification of high HR and low LR cortisol responders in female sheep can predict altered propensity to gain weight when exposed to a high-energy diet, where HR gain more adipose tissue than LR Lee et al.
Thus, at least in female sheep, data suggest that cortisol responses can be used as a physiological marker that predicts propensity to become obese.
Previous studies in women suggest that HR eat more after a stressful episode than LR Epel et al. Furthermore, HR individuals display preference for foods of high fat and sugar in response to psychological stress Tomiyama et al. Similarly, in ewes, baseline food intake is similar in LR and HR, but HR eat more following either psychosocial barking dog or immune lipopolysaccharide exposure stressors Lee et al.
In addition to altered food intake, HR ewes have reduced thermogenesis in skeletal muscle only; in response to meal feeding, post-prandial thermogenesis in skeletal muscle is greater in LR than in HR Lee et al.
This again exemplifies divergence in the control of adipose tissue and skeletal muscle thermogenesis Fig. Schematic depiction of the altered metabolic phenotype in animals selected for either high or low cortisol responsiveness.
Sheep are characterised as either high HR or low LR cortisol responders when given a standardised dose of adrenocorticotropic hormone. Animals characterized as HR have increased propensity to become obese, which is associated with perturbed control of food intake and reduced energy expenditure.
Post-prandial thermogenesis in skeletal muscle is decreased in HR compared to LR ewes. Furthermore, food intake in response to stress is greater in HR than in LR and the former are resistant to the satiety effect of alpha-melanocyte stimulating hormone aMSH.
High-cortisol-responding animals have reduced expression of the melanocortin 4 receptor MC4R in the paraventricular nucleus of the hypothalamus PVN. We propose that the decreased levels of MC4R underpin the altered metabolic phenotype and increased propensity to become obese when compared to LR.
For example, at baseline in the non-stressed resting state, HR individuals show an overall upregulation of the HPA axis, with increased expression of CRF and arginine vasopressin, but reduced expression of oxytocin in the PVN Hewagalamulage et al. In addition to altered expression of genes within the HPA axis, a key neuroendocrine feature of the LR and HR animals is altered expression of the MC3R and MC4R in the PVN Fig.
Reduced MC4R expression coincides with the development of melanocortin resistance. Central infusion of leptin reduces food intake in both LR and HR animals, but intracerebroventricular infusion of aMSH reduces food intake in LR only.
Thus, reduced MC4R expression appears to be central to the metabolic phenotype of HR that confers increased propensity to become obese in HR individuals Fig.
Interestingly, gene expression of NPY , AgRP and POMC in the arcuate nucleus is equivalent in LR and HR Hewagalamulage et al. Hence, differences in the control of food intake and thermogenesis are most likely manifest at the level of the melanocortin receptor. Indeed, previous work in sheep has shown the MC4R to be central in mediating the reduction in food intake caused by immune challenge Sartin et al.
Furthermore, in rodents, direct injection of the melanocortin agonist melanotan II into the ventromedial nucleus of the hypothalamus increases skeletal muscle thermogenesis Gavini et al.
We propose that reduced expression of the MC4R in HR animals underpins the metabolic phenotype wherein food intake is relatively increased in response to stress and reduced post-prandial thermogenesis in skeletal muscle is associated with propensity to become obese.
Historically, thermogenesis was considered to primarily occur in brown adipocytes and was solely driven by UCP1. It is now recognised that beige adipocytes and skeletal muscle also contribute to total thermogenic capacity and that thermogenesis is differentially regulated in these tissues.
Indeed, in beige adipocytes, thermogenesis occurs via three distinct mechanisms, with these being UCP1-driven mitochondrial uncoupling, futile creatine cycling and futile calcium cycling. On the other hand, in skeletal muscle, thermogenesis is associated with UCP3 and futile calcium cycling.
Unlike rodents, large mammals including sheep and pigs do not contain a defined or circumscribed brown fat depot but have dispersed brown adipocytes within traditionally white fat depots. Large animals have provided invaluable insight into alternative mechanisms of thermogenesis.
The sheep has been particularly useful in delineating the differential role of adipose tissue and skeletal muscle in the control of body weight. Furthermore, sheep models have allowed characterisation of the neuroendocrine pathways that may contribute to altered thermogenesis.
We have shown that in sheep, both skeletal muscle and BAT differentially contribute to thermogenesis and therefore total energy expenditure. Changes in thermogenesis, however, do not exclusively associate with altered gene expression at the level of the arcuate nucleus.
Indeed, decreased MC4R expression in HR animals and reduced orexin expression in the genetically obese animals coincide with altered thermogenic output. This review highlights the importance of the use of large animal models to ascertain the contribution and control of thermogenesis in multiple tissues and the relative role in the regulation of body weight.
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. This work was supported by Australian Research Council grant number DP and National Health and Medical Research Council grant number APP Animal Science 63 — Journal of Pathology and Bacteriology 91 — Obesity Reviews 19 — Molecular Metabolism 5 — Neuroendocrinology 91 — Biochimica et Biophysica Acta — Astrup A Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation.
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Cell — American Journal of Physiology R — R Banks WA Characteristics of compounds that cross the blood-brain barrier. BMC Neurology 9 S3 — S3. American Journal of Physiology: Endocrinology and Metabolism E — E Disease Models and Mechanisms 9 — Cellular and Molecular Life Sciences 73 — PLoS Genetics 2 e Cell Metabolism 25 e — Lancet — Circulation Research — American Journal of Physiology: Regulatory, Integrative and Comparative Physiology R — R International Journal of Obesity and Related Metabolic Disorders 17 Supplement 3 S78 — S Blondin DP , Daoud A , Taylor T , Tingelstad HC , Bezaire V , Richard D , Carpentier AC , Taylor AW , Harper ME , Aguer C , et al.
Journal of Physiology — International Journal of Obesity 37 — PLoS ONE 11 e Progress in Neuro-Psychopharmacology and Biological Psychiatry 35 — Metabolism 64 — Physiology Reviews 84 — Carey AL , Pajtak R , Formosa MF , Van Every B , Bertovic DA , Anderson MJ , Eikelis N , Lambert GW , Kalff V , Duffy SJ , et al.
Diabetologia 58 — Endocrinology — Cinti S The adipose organ: morphological perspectives of adipose tissues. Proceedings of the Nutrition Society 60 — Claret M , Smith MA , Batterham RL , Selman C , Choudhury AI , Fryer LG , Clements M , Al-Qassab H , Heffron H , Xu AW , et al.
Journal of Clinical Investigation — Clement K , Vaisse C , Lahlou N , Cabrol S , Pelloux V , Cassuto D , Gourmelen M , Dina C , Chambaz J , Lacorte JM , et al. Nature — Cockrem JF Individual variation in glucocorticoid stress responses in animals.
General and Comparative Endocrinology 45 — Diabetes 64 — Coppola A , Liu Z , Andrews Z , Paradis E , Roy M-C , Friedman JM , Ricquier D , Richard D , Horvath TL , Gao X-B , et al. By applying a system-analysis approach in evaluating data on the energetics of starvation and refeeding, evidence is presented here in support of the hypothesis that there are in fact two distinct control systems underlying adaptive thermogenesis.
The other is independent of the functional state of the SNS and is dictated solely by signals arising from the state of depletion of the adipose tissue fat stores; it is hence referred to as the adipose-specific control of thermogenesis, and is postulated to occur primarily in the skeletal muscle.
These two distinct control sytems for adaptive thermogenesis have been incorporated in a compartmental model of body weight and body composition regulation.
This is used to provide a mechanistic explanation as to how, during weight recovery, they can operate simultaneously but in opposite directions—with activation of thermogenesis under non-specific control being energy-dissipating, while suppression of thermogenesis under adipose-specific control being energy-conserving—and could hence explain the paradox of a high efficiency of fat recovery co-existing with an overall state of enhanced thermogenesis and hypermetabolism.
Elucidating the components of the adipose-specific control of thermogenesis ie its sensors, signals and effector mechanisms will have important implications for our understanding of body composition regulation, and hence for the development of more effective strategies in the management of cachexia and obesity.
This is a preview of subscription content, access via your institution. Department of Medicine, Institute of Physiology, University of Fribourg, Fribourg, Switzerland. Computer Unit, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
You can also search for this author in PubMed Google Scholar. Correspondence to AG Dulloo. Reprints and permissions. Dulloo, A. An adipose-specific control of thermogenesis in body weight regulation.
Int J Obes 25 Suppl 5 , S22—S29 Download citation. Published : 08 February A Quiz for Teens Are You a Workaholic? How Well Do You Sleep? Health Conditions Discover Plan Connect. Brown Fat: What You Should Know. Medically reviewed by Lisa Hodgson, RDN, CDN, CDCES, FADCES , Nutrition — By Ashley Marcin — Updated on May 22, Purpose How to get it Research Takeaway Brown fat is a healthy type of fat that is actually darker in color.
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Compostiion is a preview Thrmogenesis subscription content, log compositlon via an institution to check access. Rent Isotonic drink recipes article via Thermogenesis and body composition. Institutional subscriptions. Apfelbaum M, Bostsarron M, Lacatis D Effect of caloric restriction and excessive caloric intake on energy expenditure. Am J Clin Nutr — Google Scholar. Balke B, Ware R An experimental study of Air Force personnel. Bodu is a term that refers Intense Citrus Concentrate any HTermogenesis that generates heat. Thermogeneiss thermogenesis looks at the potential impact of our food choices, the body's regular Thermogenesis and body composition processes, and the aand required to break down that food on the body's heat production. Because this process inherently burns calories, it's often suggested that diet-induced thermogenesis should be considered part of any plan to change body composition or lose body fat. It may be used to guide nutritional recommendations to support those goals. Diet-induced thermogenesis increases how much energy you expend beyond your basal metabolic rate BMR. Thermogenesis and body composition -
Within the preoptic area, there is clearly topographical neuronal organisation as cold exposure increases c-Fos levels in GABA neurons within the ventral part of the lateral preoptic area Zhao et al. Optogenetic inhibition of this subset of GABA neurons causes hyperthermia, whereas activation of the same reduces body temperature Zhao et al.
Thus, within the preoptic area, there is an integrated network of neurons, including both GABA-ergic and leptin responsive cells, capable of sensing changes in skin temperature and modifying thermogenic output.
In addition to the aforementioned temperature-sensitive pathway, metabolic factors such as leptin, insulin and ghrelin modulate thermogenic activity via hypothalamic appetite-regulating peptides.
Blood-borne factors can diffuse across the blood brain barrier via fenestrated capillaries and act directly on neurons in the arcuate nucleus Banks Importantly, two distinct sets of neurons are found in the arcuate nucleus, being either orexigenic or those that elicit satiety. The POMC neurons are activated by leptin Elias et al.
A second population of neurons contain neuropeptide Y NPY and agouti-related protein AgRP , which stimulate food intake in response to direct stimulation by ghrelin Kamegai et al.
NPY exerts an immediate effect to stimulate food intake, primarily via action at Y1 receptors in the PVN Kask et al. On the other hand, AgRP acts as an inverse agonist at the MC4R to stimulate food intake Nijenhuis et al.
Hypothalamic appetite-regulating peptides exert reciprocal control to modulate food intake and energy expenditure, in particular BAT and muscle thermogenesis Verty et al. Indeed, pseudorabies-tracing studies show that appetite-regulating neurons of the hypothalamus ultimately project to neural networks controlling sympathetic outflow to peripheral tissues including BAT Bamshad et al.
As mentioned earlier, activation of the SNS and the release of catecholamines, in particular, noradrenaline are fundamental to BAT thermogenesis. Indeed, genetic deletion of all three β-adrenergic receptors βAR in brown adipocytes of mice causes profound obesity by negating thermogenesis Bachman et al.
Interestingly, in humans, isoprenaline a non-specific βAR treatment increases energy expenditure without an associated activation of BAT Vosselman et al.
Similarly, blockade of the βAR with propranolol had no effect on cold-induced BAT thermogenesis in humans Wijers et al. This lack of effect, however, is likely due to receptor specificity as both isoprenaline and propranolol show preferential agonistic and antagonistic affinity to the β1AR and β2AR, respectively.
Indeed, in healthy lean men, administration of the β3AR-specific agonist, mirabregon, activates BAT and causes a concurrent increase in resting metabolic rate Cypess et al. Together, these studies highlight that in humans, the β3AR is essential to catecholamine-mediated BAT thermogenesis.
In addition to catecholamines, thyroid hormones TH are notable endocrine regulators of BAT activity. Brown adipocytes contain the deiodinase type 2 DIO2 enzyme, allowing for local conversion of thyroxine T4 to triiodothyronine T3 Carvalho et al.
In rodents, TH act directly at nuclear thyroid hormone receptors located in brown adipocytes to transcriptionally upregulate UCP1 expression Weiner et al. Furthermore, clinical data demonstrate that BAT activity is higher in the subclinical hyperthyroid state than in the hypothyroid state Broeders et al.
Although the classical action of T3 is thought to be peripherally mediated, more recent studies have shown that TH can also act centrally within the hypothalamus to regulate BAT thermogenesis. Tanycytes in the mediobasal hypothalamus express DIO2 and thus convert T4 to T3 Coppola et al.
Furthermore, in mice, intracerebroventricular administration of T3 increases BAT thermogenesis via reduced hypothalamic levels of AMP kinase AMPK and subsequent activation of the SNS Lopez et al. Indeed, sub-chronic 6 days central administration of T3 leads to browning of WAT in mice Alvarez-Crespo et al.
To date, much of the work defining the regulation of thermogenesis and its contribution to energy balance has been in rodents.
This has provided invaluable information and understanding of the neuroendocrine mechanisms that control thermogenesis. More recently, a number of large animal models have been employed including pigs and sheep, which provide further insight into the role of thermogenesis in long-term regulation of body weight in mammalian species.
It is well recognised that pigs lack a functional UCP1 protein Hou et al. Pigs, specifically those belonging to the Suidae species, do not have exons 3—5 of the UCP1 gene, rendering animals prone to hypothermia-induced death as neonates Berg et al.
With only exons 1 and 2, UCP1 can still be transcribed; however, protein translation does not occur Hou et al. Hence, previous histological studies failed to detect UCP1 protein immunoreactivity at baseline Rowlatt et al. It has since been proposed that pigs do indeed possess functional BAT; however, adaptive thermogenesis occurs via UCP1-independent mechanisms Ikeda et al.
Indeed, recent work comparing cold-tolerant Tibetan pigs to cold-sensitive Bama pigs has provided direct evidence of adaptive thermogenesis in subcutaneous sWAT and perirenal WAT Lin et al. Furthermore, morphological studies show that in response to cold exposure, subcutaneous adipose tissue displays evidence for beige cell recruitment with an increase in multilocular adipocytes, increased mitochondrial DNA copy number and increased expression of PGC1a and the beige cell marker CD Wu et al.
Furthermore, in Tibetan pigs cold tolerant , cold exposure increased the expression of the UCP3 gene and protein in isolated subcutaneous adipocytes and this is associated with increased uncoupled respiration, providing evidence to suggest an increase in UCP3-driven thermogenesis Lin et al.
Role of thermogenesis in determining cold tolerance in pigs. Tibetan pigs are cold tolerant and this coincides with the recruitment of beige adipocytes in subcutaneous WAT in response to cold exposure. Although pigs do not that express functional uncoupling protein UCP 1, adipocytes exhibit UCP3 and this mediates mitochondrial uncoupling and adipose tissue thermogenesis.
The contribution of UCP3 to brown fat thermogenesis has been contentious and appears to be dependent on the species studied. In mice, earlier work suggested that BAT thermogenesis was dependent on UCP1 Matthias et al. Despite this, hamsters that lack functional UCP3 specifically in brown adipocytes have increased propensity to weight gain, which is indicative of a reduction in energy expenditure Fromme et al.
Although innate differences in UCP3 expression in adipose tissue of pigs have been linked to cold tolerance, to date, there are no data on BAT-specific UCP3 function and the control of body weight in this species.
In addition to UCP3-associated uncoupling and thermogenesis, recent data suggest that SERCA-driven beige cell thermogenesis also occurs in pigs. Indeed, the work by Ikeda et al. Ikeda et al. Retroviral expression of PRDM in subcutaneous porcine adipocytes increases the expression of beige-cell-specific markers including CIDEA and TMEM26 Ikeda et al.
Furthermore, decreased SERCA2b expression reduced basal and noradrenaline-induced oxygen consumption and extracellular acidification rates in isolated pig adipocytes Ikeda et al. Thus, it is now clear that adipose tissue thermogenesis and the associated energy expenditure are not solely mediated via UCP1 and mitochondrial uncoupling, but in fact, a number of cellular pathways, across both adipose tissue and skeletal muscle, act in concert to determine total thermogenic potential.
In lambs, the expression of UCP1 is maximal in perirenal adipose tissue on the first postnatal day, rapidly declining with the expansion of WAT Symonds , Pope et al. Mapping of UCP1 mRNA in lambs shows abundant expression in sternal and retroperitoneal adipose depots compared to omental fat, which is a predominantly WAT depot Symonds et al.
Indeed, adult sheep retain UCP1 expression in both sternal and retroperitoneal fat and this coincides with post-prandial heat production, albeit this response is greater in the sternal fat depot Henry et al. This coincides with the expression of UCP1 protein, where UCP1-positive brown-like adipocytes were only detectable in sternal adipose tissue of adult ewes Henry et al.
Data logger temperature probes have been employed to measure longitudinal heat production in multiple tissues to index thermogenic output in sheep. Sheep are a grazing species and therefore do not display typical meal-associated excursions such as changes in ghrelin secretion.
Despite this, temporal food restriction in sheep entrains a pre-prandial rise in ghrelin Sugino et al. Furthermore, post-prandial thermogenesis in both skeletal muscle and retroperitoneal adipose depots is markedly enhanced by intracerebroventricular infusion of leptin Henry et al.
Thus, in spite of relatively low levels of UCP1 in adult sheep, skeletal muscle and specific adipose depots retain thermogenic capacity.
Over recent years, we have utilised the sheep to dissect the differential roles of adipose tissue and skeletal muscle thermogenesis in the long-term control of body weight, which is discussed in detail in the following section. Similar to other species, ovine body weight can be readily manipulated through dietary management Henry et al.
Sheep are ruminants and thus body weight is increased through feeding a high-energy diet enriched in lupin grain and oats. Diet-induced obesity, however, is not associated with any change in heat production in adipose tissues or skeletal muscle of sheep Henry et al.
On the other hand, long-term food restriction and low body weight are associated with a homeostatic decrease in thermogenesis in sternal and retroperitoneal adipose tissue and skeletal muscle Henry et al.
Importantly, similar to humans, the reduction in thermogenesis caused by food restriction and low body weight is still evident at one year post-weight loss, which suggests that homeostatic changes in thermogenesis contribute to impaired weight loss and increased long-term weight regain Henry et al.
Effect of chronic food restriction and weight loss on adaptive thermogenesis in ewes. Tissue temperature recordings show that caloric restriction and low body weight cause a homeostatic decrease in night time thermogenesis in ovariectomised ewes.
This metabolic adaptation occurs in both sternal adipose tissue adipose tissue enriched in uncoupling protein 1 and skeletal muscle and to a lesser extent in retroperitoneal adipose tissue.
The reduction in thermogenesis is associated with increased expression of neuropeptide Y NPY in the arcuate nucleus and melanin-concentrating hormone MCH in the lateral hypothalamus.
The homeostatic reduction in thermogenesis is coordinated by the hypothalamus. Long-term weight loss in ovariectomised ewes increases the expression of the orexigenic neuropeptides NPY in the arcuate nucleus and melanin-concentrating hormone MCH in the lateral hypothalamus LH to increase hunger and reduce energy expenditure Henry et al.
Regarding the anorexigenic melanocortin pathway, the effect of low body weight on the expression of POMC is controversial with data showing a decrease Backholer et al. This is not surprising since POMC is the precursor to multiple neuropeptides, only one of which includes aMSH and the ultimate end product is dependent on post-translational processing Mountjoy On the other hand, increased Agrp and Npy expression and reduced Pomc mRNA have been observed in rodents Bi et al.
Thus, weight-loss-induced changes in hypothalamic gene expression are likely to reduce thermogenesis, whilst causing a concurrent increase in hunger drive. This represents a homeostatic mechanism to protect against weight loss and promote weight regain in calorie-restricted individuals.
Animals were originally selected for innate differences in adiposity by measuring back fat thickness and two lines were created via selective breeding strategies.
A key feature of the genetically lean and obese sheep is an inherent difference in the growth hormone GH axis, where lean animals have increased mean GH concentration in plasma and an associated increase in pituitary gland weight Francis et al.
The increase in pituitary gland weight is primarily due to a greater number of cells in the lean animals Francis et al. Furthermore, expression of GH and the GH secretagogue receptor GHSR is greater in genetically lean sheep, indicating differential responses to ghrelin, an agonist of the GHSR French et al.
This suggests that innate differences in the set-point of the GH axis may underpin differences in adiposity in the genetically lean and obese sheep; however, this is only one aspect that could contribute to this phenotype.
Interestingly, food intake is similar in genetically lean and obese sheep as is the expression of POMC, Leptin Receptor and NPY in the arcuate nucleus. On the other hand, lean animals have elevated post-prandial thermogenesis in retroperitoneal adipose tissue and this coincides with increased expression of UCP1 in this tissue Henry et al.
The divergence in thermogenesis is specific to adipose tissue since post-prandial thermogenesis is similar in genetically lean and obese animals Henry et al. Despite similar expression of appetite-regulating peptides in the arcuate nucleus of the hypothalamus, genetically lean sheep have increased expression of MCH and pre-pro-orexin ORX in the LH compared to obese animals Anukulkitch et al.
While both neuropeptides are considered orexigenic Shimada et al. Deletion of MCH in mice results in hypophagia and a lean phenotype Shimada et al. Orexin is critical in the embryonic development of BAT in mice Sellayah et al. Thus, increased expression of ORX in the LH of lean sheep may be an important physiological determinant of increased thermogenesis in retroperitoneal fat and the associated changes in adiposity.
It is widely recognised that there is marked variation in the glucocorticoid response to stress or activation of the hypothalamo-pituitary adrenal HPA axis Cockrem , Walker et al.
The activity of the HPA axis in response to stress is impacted on by age Sapolsky et al. Nonetheless, in any given population individuals can be characterised as either high HR or low LR glucocorticoid responders Epel et al. It is important to note that female LR and HR sheep have similar basal plasma cortisol concentration and divergence in glucocorticoid secretion only occurs in response to ACTH or stress Lee et al.
Previous studies have suggested that obesity itself causes perturbation of the HPA axis with impaired glucocorticoid-negative feedback Jessop et al. Furthermore, cortisol directly impacts on metabolic function; however, this will not be addressed in the current review.
Initial studies in rams show that high cortisol response to adrenocorticotropin ACTH is associated with lower feed-conversion efficiency Knott et al.
Furthermore, in rams, adiposity is correlated to cortisol responses to ACTH Knott et al. More recent work shows that identification of high HR and low LR cortisol responders in female sheep can predict altered propensity to gain weight when exposed to a high-energy diet, where HR gain more adipose tissue than LR Lee et al.
Thus, at least in female sheep, data suggest that cortisol responses can be used as a physiological marker that predicts propensity to become obese. Previous studies in women suggest that HR eat more after a stressful episode than LR Epel et al.
Furthermore, HR individuals display preference for foods of high fat and sugar in response to psychological stress Tomiyama et al. Similarly, in ewes, baseline food intake is similar in LR and HR, but HR eat more following either psychosocial barking dog or immune lipopolysaccharide exposure stressors Lee et al.
In addition to altered food intake, HR ewes have reduced thermogenesis in skeletal muscle only; in response to meal feeding, post-prandial thermogenesis in skeletal muscle is greater in LR than in HR Lee et al.
This again exemplifies divergence in the control of adipose tissue and skeletal muscle thermogenesis Fig. Schematic depiction of the altered metabolic phenotype in animals selected for either high or low cortisol responsiveness. Sheep are characterised as either high HR or low LR cortisol responders when given a standardised dose of adrenocorticotropic hormone.
Animals characterized as HR have increased propensity to become obese, which is associated with perturbed control of food intake and reduced energy expenditure. Post-prandial thermogenesis in skeletal muscle is decreased in HR compared to LR ewes.
Furthermore, food intake in response to stress is greater in HR than in LR and the former are resistant to the satiety effect of alpha-melanocyte stimulating hormone aMSH.
High-cortisol-responding animals have reduced expression of the melanocortin 4 receptor MC4R in the paraventricular nucleus of the hypothalamus PVN. We propose that the decreased levels of MC4R underpin the altered metabolic phenotype and increased propensity to become obese when compared to LR.
For example, at baseline in the non-stressed resting state, HR individuals show an overall upregulation of the HPA axis, with increased expression of CRF and arginine vasopressin, but reduced expression of oxytocin in the PVN Hewagalamulage et al.
In addition to altered expression of genes within the HPA axis, a key neuroendocrine feature of the LR and HR animals is altered expression of the MC3R and MC4R in the PVN Fig.
Reduced MC4R expression coincides with the development of melanocortin resistance. Central infusion of leptin reduces food intake in both LR and HR animals, but intracerebroventricular infusion of aMSH reduces food intake in LR only.
Thus, reduced MC4R expression appears to be central to the metabolic phenotype of HR that confers increased propensity to become obese in HR individuals Fig. Interestingly, gene expression of NPY , AgRP and POMC in the arcuate nucleus is equivalent in LR and HR Hewagalamulage et al.
Hence, differences in the control of food intake and thermogenesis are most likely manifest at the level of the melanocortin receptor. Indeed, previous work in sheep has shown the MC4R to be central in mediating the reduction in food intake caused by immune challenge Sartin et al.
Furthermore, in rodents, direct injection of the melanocortin agonist melanotan II into the ventromedial nucleus of the hypothalamus increases skeletal muscle thermogenesis Gavini et al. We propose that reduced expression of the MC4R in HR animals underpins the metabolic phenotype wherein food intake is relatively increased in response to stress and reduced post-prandial thermogenesis in skeletal muscle is associated with propensity to become obese.
Historically, thermogenesis was considered to primarily occur in brown adipocytes and was solely driven by UCP1. It is now recognised that beige adipocytes and skeletal muscle also contribute to total thermogenic capacity and that thermogenesis is differentially regulated in these tissues.
Indeed, in beige adipocytes, thermogenesis occurs via three distinct mechanisms, with these being UCP1-driven mitochondrial uncoupling, futile creatine cycling and futile calcium cycling. On the other hand, in skeletal muscle, thermogenesis is associated with UCP3 and futile calcium cycling.
Unlike rodents, large mammals including sheep and pigs do not contain a defined or circumscribed brown fat depot but have dispersed brown adipocytes within traditionally white fat depots. Large animals have provided invaluable insight into alternative mechanisms of thermogenesis.
The sheep has been particularly useful in delineating the differential role of adipose tissue and skeletal muscle in the control of body weight.
Furthermore, sheep models have allowed characterisation of the neuroendocrine pathways that may contribute to altered thermogenesis.
We have shown that in sheep, both skeletal muscle and BAT differentially contribute to thermogenesis and therefore total energy expenditure. Changes in thermogenesis, however, do not exclusively associate with altered gene expression at the level of the arcuate nucleus. Indeed, decreased MC4R expression in HR animals and reduced orexin expression in the genetically obese animals coincide with altered thermogenic output.
This review highlights the importance of the use of large animal models to ascertain the contribution and control of thermogenesis in multiple tissues and the relative role in the regulation of body weight.
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. This work was supported by Australian Research Council grant number DP and National Health and Medical Research Council grant number APP Animal Science 63 — Journal of Pathology and Bacteriology 91 — Obesity Reviews 19 — Molecular Metabolism 5 — Neuroendocrinology 91 — Biochimica et Biophysica Acta — Astrup A Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation.
Acta Endocrinologica Supplement S9 — S American Journal of Physiology E — E Science — Neuroendocrinology 91 27 — Journal of Biological Chemistry — Bal NC , Maurya SK , Sopariwala DH , Sahoo SK , Gupta SC , Shaikh SA , Pant M , Rowland LA , Bombardier E , Goonasekera SA , et al. Nature Medicine 18 — Journal of Neuroendocrinology 29 e Terjung RL, Winder WW Exercise and thyroid function.
Med Sci Sports 7: 20— Weber G, Kartodiharjio W, Klissouras V Growth and physical training with reference to heredity. Wilmore JH Training for sport and activity.
Allyn and Bacon, Boston, p Download references. of Psychology, University of New Hampshire, , Durham, NH, USA. of Home Economics, University of New Hampshire, , Durham, NH, USA.
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The study was supported by a grant from Metabolife Inc, San Diego, CA, USA. The dietary supplements containing the ingredients examined in the present paper were manufactured by Alpine Health Products, Salt Lake City, Utah, and are not commercially available.
Department of Human Nutrition, Centre for Advanced Food Studies, The Royal Veterinary and Agricultural University, Frederiksberg C, Denmark.
Department of Clinical Physiology and Nuclear Medicine, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark. You can also search for this author in PubMed Google Scholar. Correspondence to A Belza.
Reprints and permissions. Belza, A. Body fat loss achieved by stimulation of thermogenesis by a combination of bioactive food ingredients: a placebo-controlled, double-blind 8-week intervention in obese subjects. Int J Obes 31 , — Download citation. Received : 30 December Revised : 14 March Accepted : 16 March Published : 25 April Issue Date : 01 January Anyone you share the following link with will be able to read this content:.
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Abstract Background: A combination of tyrosine, capsaicin, catechines and caffeine may stimulate the sympathetic nervous system and promote satiety, lipolysis and thermogenesis.
Objective: To investigate the acute and subchronic effect of a supplement containing the above mentioned agents or placebo taken t. Design: In total, 80 overweight—obese subjects body mass index Results: Weight loss during the induction phase was 6.
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Metabolic adaptation to weight Diuretic effect on gout relates an Thermogenesis and body composition weight control, obesity and malnutrition. Adaptive thermogenesis AT refers to changes in Therjogenesis and Thermogenesis and body composition energy Thermogenessi REE and nREE which are independent from changes in fat-free mass FFM and FFM composition. AT differs in response to changes in energy balance. With negative energy balance, AT is directed towards energy sparing. It relates to a reset of biological defence of body weight and mainly refers to REE. After weight loss, AT of nREE adds to weight maintenance.
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