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Exercise-Mediated Effects on White and Brown Adipose Tissue Plasticity and Metabolism

Sepa-Kishi, Diane M.; Ceddia, Rolando B.

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Exercise and Sport Sciences Reviews: January 2016 - Volume 44 - Issue 1 - p 37-44
doi: 10.1249/JES.0000000000000068
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Obesity has reached global epidemic proportions and is threatening the economic sustainability of the health care system of many countries worldwide. This is related largely to the fact that obesity is a major risk factor for the development of many debilitating chronic diseases such as type 2 diabetes (T2D), coronary artery disease, hypertension, stroke, and certain types of cancer (18). Importantly, despite all efforts dedicated to curb obesity in the population, the results have been disappointing. In fact, there is great pessimism about how successful obesity treatment can be. Weight gain often occurs gradually across decades (∼1 lb yr-1), making it difficult for most people to actually perceive its specific causes (18). In fact, it has been shown that a consistent positive energy imbalance of as little as 50 to 100 kcal d-1 may be sufficient to cause gradual weight gain that ends up leading to overweight/obesity in most people (18). This is aggravated further by the fact that people show poor adherence to lifestyle modifications designed to limit food intake (diet) and increase energy expenditure (exercise). Thus, great interest exists in the development of new therapies to be used in the fight against obesity that are safe and more efficient than the ones currently available. In this scenario, the recent discovery that adult humans have thermogenically competent brown adipose tissue (BAT) (6) has sparked great interest in the possibility of developing strategies that target this tissue to promote energy dissipation and prevent fat storage in the white adipose tissue (WAT).

Several studies also have reported recently that chronic endurance exercise (3,34) has the ability to promote the expression of thermogenic genes in the WAT, also known as “browning” of the WAT, and potentially contribute to increase whole-body energy expenditure (3,34). In fact, browning of the subcutaneous (SC) inguinal (Ing) fat depot has been reported to be accompanied by an increase in resting energy expenditure of approximately 14%–17% in endurance-trained rats compared with sedentary controls. Furthermore, such effects on resting energy expenditure occurred despite exercise inducing significant reductions in tissue mass and thermogenic capacity of classical BAT (34). These findings established a novel and unexplored relationship between endurance exercise and browning of WAT, with important potential implications for the regulation of whole-body energy homeostasis, as well as for the treatment of metabolic disorders such as obesity and T2D. In this article, we discuss how chronic endurance exercise regulates thermogenic activity in BAT and WAT, as well as how this potentially affects resting metabolic rate (RMR), adiposity, energy availability, and the ability of the organism to cope with exercise-induced heat production. In this context, we put forward the hypothesis that exercise-induced browning of the SC WAT provides a mechanism that shifts thermogenesis from core to peripheral regions of the body. This allows the organism to make adjustments to its metabolic rate to accommodate eventual changes in energy availability through diet-induced thermogenesis (DIT) while simultaneously coping with the stress of chronically increased heat production through exercise.

Structural and Functional Characteristics of White and Brown Adipose Tissues

The adipose tissue can be classified generally into white (WAT) and brown (BAT). The WAT can be subdivided into SC and internal (visceral and nonvisceral) compartments according to its topographical location (31). In humans, the SC and internal fat compartments comprise approximately 80% and 20% of the total fat stored in the body, respectively (31). The white adipocyte is the most abundant cell (35%–75% of total cells) found in the adipose tissue, with the remaining being stromal vasculature tissue containing fibroblasts, endothelial cells, blood cells, macrophages, pericytes, and preadipocytes among others (5). A mature white adipocyte has a unilocular appearance because of the presence of a single lipid droplet surrounded by a rim of cytoplasm and offset nucleus (Fig. 1). The size of the lipid droplet changes mostly by alterations in its triglyceride (TG) content. White adipocytes contain a small number of thin and elongated mitochondria with randomly oriented cristae, and these cells display low oxidative capacity (5). Thus, the white adipocyte is essentially specialized in lipid synthesis for storage under conditions of energy surplus and TG breakdown (lipolysis) for exportation of fatty acids (FA) when the availability of food is limited (e.g., fasting) and/or energy expenditure is increased (e.g., exercise) (9). The WAT also is considered an endocrine organ due to its ability to secrete a large number of biologically active molecules (adipokines). Through the release of these adipokines, the WAT can regulate whole-body energy homeostasis by coordinating centrally and peripherally mediated metabolic alterations (9).

Figure 1
Figure 1:
Structural characteristics of rat white (epididymal fat pad), classical brown (interscapular brown adipose tissue), and beige (subcutaneous (SC) inguinal fat pad) adipocytes. The typical appearance of a white adipocyte is a cell with few mitochondria and most of its cytoplasmic area occupied by a single lipid droplet (LD) (unilocular) with the nucleus and organelles pushed to the side. Brown adipocytes are polygonal cells with several LD (multilocular adipocytes) distributed throughout the cytoplasm that is populated densely with mitochondria and lysosomes. The mitochondria in brown adipocytes are rich in uncoupling protein-1 (UCP-1) that uncouples oxidative phosphorylation from adenosine triphosphate synthesis to produce heat. Beige adipocytes are depicted as clusters of multilocular UCP-1+ cells normally found within specific compartments of the white adipose tissue (e.g., SC fat depot) and display brownlike functional characteristics.

The BAT is composed primarily of brown adipocytes, which are mostly polygonal cells (ranging from 15 to 50 μm in diameter) with a central nucleus and several lipid droplets in the form of small vacuoles (multilocular adipocytes). Contrary to white, brown adipocytes have abundant cytoplasm densely populated with mitochondria and lysosomes, which confer the brown color to the tissue (Fig. 1). Mitochondria in brown adipocytes are large, spherical, and packed with laminar cristae (5). In addition, the densities of the capillary network and of the nerve supply are much greater in BAT than WAT (4). The main feature of a brown adipocyte is that β-oxidation is uncoupled from adenosine triphosphate (ATP) formation due to the presence of uncoupling protein-1 (UCP-1), which leaks protons across the inner mitochondrial membrane, bypassing ATP synthesis. The energy stored in the proton electrochemical gradient is converted to heat instead of ATP. Because UCP-1 is mainly present in brown adipocytes, this protein is considered to be a unique marker of this cell type (4). Temperatures below thermoneutrality trigger thermogenesis in brown adipocytes via activation of the sympathetic nervous system (SNS). BAT is extremely well vascularized so that the blood is warmed as it passes thorough the active tissue, helping to distribute the heat produced (4).

Importantly, the activity of UCP-1 in brown fat cells is controlled by SNS activity through a process mediated by a lipolysis-induced increase in intracellular FA concentrations (4). FA are thought to interact with UCP-1 and remove the inhibitory effect of cytosolic nucleotides (ATP, adenosine diphosphate, guanosine triphosphate, and guanosine diphosphate) on this protein, leading to uncoupled respiration and heat production (4). Thus, alterations in signaling events that control lipolysis also can regulate thermogenesis in BAT. It seems that of all β-adrenergic receptors (β-AdR), the β3 isoform is the one primarily responsible for UCP-1 activation and heat production in BAT (4). Thyroid hormones, particularly triiodothyronine (T3), also have well-known thermogenic properties. T3 availability in brown fat cells is regulated by type 2 deiodinase (D2), which is expressed highly in BAT. In fact, mice lacking D2 in brown fat cells have impaired catecholamine-stimulated UCP-1 expression and display impaired cold tolerance (13).

Plasticity Between WAT and BAT

Despite major structural and functional differences between WAT and BAT, these tissues show remarkable plasticity and can acquire features of one another under specific physiological conditions (Fig. 1). This was demonstrated originally in WAT of mice that acquired a BAT-like phenotype when exposed to cold, a phenomenon that was reversible and characterized by an increase in the number of capillaries, nerves, and UCP-1+ cells in the WAT (5). These brownlike fat cells found in the WAT have been named “brite” (brown-in-white) or beige adipocytes (Fig. 1). Interestingly, the capacity to recruit and induce beige adipocytes differs among various white fat depots. In rats and mice it seems that the SC Ing fat pad is the one more prone to undergoing browning (5,34). The mechanisms underlying this depot-specific propensity of WAT to undergo browning under cold or exercise conditions remain poorly understood. It seems that the ability to undergo browning is related to how much each WAT depot is capable of activating at least two processes: 1) transdifferentiation of mature unilocular white adipocytes into multilocular brownlike cells, which could be triggered by the induction of a thermogenic futile cycle of lipolysis and lipogenesis (1); and 2) de novo adipogenesis to form new cells that are thermogenically competent much like classical brown adipocytes (27).

The important aspect of functionally converting white adipocytes into brown is that it amplifies the possibility of inducing energy dissipation beyond thermogenesis that is attributed classically to specific depots of typical BAT. In rodents and humans, typical BAT is found in proximity to the heart so that heat produced by brown adipocytes can be distributed quickly and effectively for regulation of body temperature (4). Importantly, the SC WAT compartment is located peripherally, and elevated ectopic expression of UCP-1 in this tissue may lead to an increase in energy dissipation without necessarily affecting core body temperature. Therefore, browning of white adipocytes located in the SC compartment may be important for the regulation of WAT metabolism and adiposity under conditions that affect whole-body energy balance such as diet and exercise. In addition, the potential to manipulate the inherent plasticity of the adipose organ is important because animals with more BAT are more resistant to obesity and T2D (10,33), whereas those without functional BAT are prone to obesity and T2D (7). New evidence is emerging that human abdominal and thigh SC WAT increase thermogenic genes seasonally and acutely in response to a cold stimulus, a response that is inhibited by obesity and inflammation (15). Furthermore, it also has been demonstrated that human adipose-derived stromal/progenitor cells from SC WAT can be converted efficiently into beige adipocytes, which on activation undergo UCP-1–dependent thermogenesis (2). This provides support to the idea that both rodents and humans have the ability to shift WAT metabolism toward a BAT-like phenotype on specific stimuli.

Molecular and Physiological Regulators of Plasticity Between WAT and BAT

Classical or typical brown fat, such as the interscapular BAT (iBAT) in rodents and the supraclavicular in humans, has been proposed to derive from a Myf5+ muscle-like cellular lineage, whereas beige adipocytes found within the WAT seem to originate from one or more Myf5- lineage(s) (29). Thus, even at the precursor stage, inducible thermogenic beige fat cells seem to be fundamentally different from the other fat cells present in the WAT that do not become beige. To complicate matters further, lineage tracing analysis (27) has revealed that each WAT depot contains adipocyte progenitor cells apparently arising from Myf5+ precursors, although the number of which varies depending on depot location. This also could be one of the reasons why certain WAT fat depots are more prone than others to undergoing browning on exposure to cold or chronic endurance exercise.

The molecular mechanism mediating the acquisition of a BAT-like phenotype by WAT in cold-acclimatized mice involves upregulation of peroxisome proliferator–activated receptor-γ (PPAR-γ) coactivator-1α (PGC-1α) and PRD1-BF-1-RIZ1 homologous domain containing 16 (PRDM16) in visceral and SC WAT (30) (Fig. 2). PRDM16 is a histone methyltransferase zinc-finger–containing protein that also interacts directly with transcription factors such as PPARγ, PPARα, CCAT/enhancer binding proteins, and zinc-finger protein 516 that are key regulators of adipogenesis (14). Interestingly, PRDM16 expression in white fat precursor cells represses gene expression of selective markers of white adipocytes (e.g., resistin, angiotensinogen, annexin A1, endothelin receptor type A, and WDNM1-like protein) in a C-terminal-binding protein-1 and -2-dependent manner (14). Also, PRDM16 induces the expression of brown fat-specific genes (PGC-1α and UCP-1) in brown and beige adipocytes by interacting directly with the MED1 subunit of the mediator complex and by enhancing Ucp-1 gene expression (11). In fact, PRDM16 seems to work as a coregulatory protein that can function as a bidirectional switch in brown fat development through multiple protein interactions (14). It has been demonstrated that transgenic expression of PRDM16 in white adipocytes selectively transformed the SC WAT into a brownlike tissue (30). Furthermore, the presence of beige adipocytes in the SC WAT of aP2-PRDM16 mice was associated with a rise in whole-body energy expenditure and suppression of weight gain in response to a high-fat (HF) diet (30). Importantly, PRDM16 was required for the induction of a thermogenic gene program in isolated SC adipocytes and also in vivo (30). In this scenario, it seems that increased expression and activity of PGC-1α promote mitochondrial biogenesis, whereas increased PRDM16 expression induces adipocyte differentiation toward the brown phenotype (30). Together, these transcriptional regulators can induce a nearly complete brown fat genetic program and seem to play a major role in the conversion of WAT into BAT, although it is still not clear whether alteration of PRDM16 expression/activity is required for the browning effect of chronic endurance exercise to occur (24) (Fig. 2). Because PRDM16 regulates the induction of brown fat-specific genes during the differentiation process, it could be that the role of this transcriptional regulator in exercise-induced browning of the WAT is restricted to early stages of exercise training. Thus, a time-course assessment of PRDM16 during exercise training may be required to reveal its role and relevance for the browning effect of exercise on the WAT.

Figure 2
Figure 2:
Exercise and diet-induced obesity exert opposing effects on the thermogenic capacity of white and beige adipocytes. Exercise promotes the expression of proteins that turn on a brown fat genetic program that converts mature white adipocytes (transdifferentiation) and precursor cells present in the white adipose tissue (WAT) into beige adipocytes. The latter are more densely populated with mitochondria, have a multilocular appearance, are enriched with uncoupling protein-1, and are thermogenically competent. Conversely, diet-induced obesity reduces the expression of thermogenic proteins, attenuates the browning effect of exercise, and promotes fat deposition in the WAT. The PRD1-BF-1-RIZ1 homologous domain containing 16 (PRDM16) is a critical molecular regulator of brown adipocyte differentiation, although its effect on the browning effect of exercise on the WAT remains to be elucidated. AMPK, adenosine monophosphate-activated protein kinase; ATGL, adipose triglyceride lipase; PGC-1α, PPAR-γ coactivator-1α; PPAR, peroxisome proliferator-activated receptor.

Exercise-induced browning of the SC Ing WAT is accompanied by increased adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and PGC-1α and adipose TG lipase (ATGL) contents in rats exposed to chronic endurance training (34). Upregulation of these proteins also was accompanied by increases in UCP-1 content and oxidative capacity in the SC Ing WAT (34) (Fig. 2). AMPK has been reported to promote PGC-1α phosphorylation and activation in skeletal muscle cells (12), and PGC-1α has been shown to be required for exercise-induced upregulation of UCP-1 in mouse WAT (24), suggesting that activation of the AMPK-PGC-1α pathway in adipocytes could be sufficient to cause a browning effect in WAT and increase whole-body energy expenditure. We have demonstrated previously that prolonged treatment with the AMPK activator AICAR caused a significant increase in PGC-1α expression (8), as well as mitochondrial content, and fatty acid oxidation in the WAT of these animals (9). Even though whole-body energy expenditure was increased and adiposity was reduced in AICAR-treated rats, UCP-1 content in the SC and visceral fat depots was similar to that of control rats (9). Thus, the increase in whole-body energy expenditure in AICAR-treated rats did not seem to have been caused by increased thermogenic activity within the WAT. Rather, it was the increase in leptin sensitivity and spontaneous physical activity also found in AICAR-treated rats that likely led to elevated energy expenditure and reduced adiposity in these animals (9). The results of these studies indicate that conditions promoting energy dissipation in the WAT (e.g., exercise, cold exposure, and prolonged pharmacological activation of AMPK) share some common molecular mediators. However, the browning effect that is accompanied by increased UCP-1 content within the WAT seems to require the activation of specific, but yet poorly understood, signaling pathways.

Much debate currently exists regarding whether browning of the WAT occurs as an adaptive response of preexisting white adipocytes that increase UCP-1 expression and become multilocular (transdifferentiation) (1) or caused by de novo adipogenesis (27) involving the recruitment of undifferentiated cells within the WAT that develop into new thermogenically competent beige/brite cells. The former process would require turning on a thermogenic program in fully mature adipocytes, whereas in the latter, an entirely new brownlike fat cell would have to be formed. Despite overlapping to some extent, the signaling steps involved in these two processes could differ significantly. Addressing this issue is important to establish the best approach to promote browning of the WAT for therapeutic purposes.

It was proposed initially that irisin, a PGC-1α-driven myokine released by the cleavage of the ectodomain of fibronectin-domain containing protein 5 (FNDC5) during exercise, would signal to white adipocytes in the SC adipose tissue compartment to undergo browning (3). However, the role of irisin in exercise-induced browning of the WAT has been challenged because muscle FNDC5 content and circulating irisin have not been consistently increased with endurance exercise in humans (22). This is supported by our findings that chronic endurance exercise induced browning of the SC WAT without increasing FNDC5 content in skeletal muscle or circulating irisin levels in rats (34). However, it is important to note that FNDC5 content was increased robustly in the SC Ing WAT of endurance-trained rats, an effect that was attenuated by HF diet-induced obesity (34). This suggests that browning of the SC Ing WAT could have occurred by FNDC5 signaling locally instead of through the release of irisin. Based on crystal structure analysis, it has been predicted that a tight dimerization of the FNDC5 ectodomain may form intracellular and/or intercellular cell surface dimers, which could trigger autocrine or paracrine signaling independently of cleavage and release of irisin in the circulation (28). This is a potential mechanism by which exercise induced a pronounced browning effect in the SC Ing fat, whereas HF feeding attenuated it (34).

Physiologically, BAT is activated by the SNS through the release of catecholamines, which act mainly via β3-AdR signaling (4). Thus, β3-AdR activation triggers cold- and diet-induced thermogenesis in BAT as a consequence of SNS activation and catecholamine release. In response to moderate- to high-intensity endurance training, SNS activity is increased, leading to sustained elevated levels of circulating catecholamines (20). In our model, exercise intensity was kept constant at 70%–85% of peak V˙O2 throughout the training period, so circulating catecholamines are expected to be increased during exercise bouts. This was confirmed by our findings that circulating epinephrine was increased during an exercise bout of similar relative intensity (80% of peak V˙O2) at the beginning and after 3 and 6 wk of endurance training (21). Therefore, it is surprising that thermogenic capacity was reduced markedly in iBAT and peri-aortic BAT (aBAT) of endurance-trained rats (34), despite repeated daily transient increases in circulating epinephrine. This suggests that chronic endurance training downregulates β3-AdR in classical BAT. Previous studies have indeed demonstrated that prolonged oral administration of the thermogenic β-AdR agonist Ro 16-8714 to rats selectively downregulated mRNA expression and the number of β3-AdR on the membrane of brown adipocytes from the iBAT (23). This could act as a tissue-specific desensitization mechanism to prolonged β-AdR stimulation. This is consistent with our findings that the SC Ing fat depot acquired a brownlike phenotype, whereas in iBAT and aBAT, thermogenic capacity was markedly suppressed in endurance-trained rats (34). This may have occurred through downregulation and upregulation of β-AdR signaling in classical BAT and SC WAT, respectively, by repeated transient SNS activation through chronic endurance exercise. There also is the possibility that exercise alters α-AdR activity either directly at the tissue level or via brain-mediated effects that lead to antagonistic regulation of thermogenesis in classical BAT and SC WAT. There is evidence that α2-AdR agonists acting through a brain-mediated mechanism can inhibit BAT sympathetic nerve activity and thermogenesis in rats (17). However, it is still not clear how the modulation of β-/α-AdR activity could lead to antagonistic regulation of thermogenic capacity in classical BAT versus SC WAT through chronic endurance exercise. Thus, this remains largely speculative, and additional studies are required to test these hypotheses.

Exercise- and Diet-Induced Alterations in Mass and Function of Typical BAT

A large amount of heat is produced as a consequence of muscle contractions, which is expected to cause a reduction in BAT activity during bouts of exercise. Previous studies have reported that the mass, Ucp-1 mRNA (35), and thermogenic activity (16) of iBAT were reduced markedly in rodents exposed to chronic endurance training. Our recent study (34) also showed that male rats exposed to 8 wk of progressive treadmill running had approximately 40% lower iBAT mass than sedentary counterparts. This was accompanied by marked reductions in UCP-1 content (65%) and palmitate oxidation (30%) in iBAT homogenates of endurance-trained rats (34). Furthermore, microscopic analysis revealed that a large number of unilocular lipid droplets accumulated in iBAT of rats chronically exposed to endurance training. These are compatible with reduced thermogenic activity in this classical BAT under a condition where heat production through muscle contractions is increased transiently but regularly (34) (Fig. 3).

Figure 3
Figure 3:
Chronic endurance exercise causes opposing effects on the thermogenic capacity of centrally located classical brown adipose tissue (BAT) (interscapular BAT (iBAT) and peri-aortic BAT (aBAT)) and peripherally located subcutaneous inguinal (SC Ing) fat. It seems that chronic endurance exercise causes a shift in thermogenic activity from core to superficial regions of the body. Images of iBAT, aBAT, heart, and SC Ing fat are from either sedentary (left panels) or endurance-trained rats (8 wk of treadmill running, right panels). UCP-1, uncoupling protein-1.

Besides playing a crucial role in body temperature regulation, classical BAT in rodents has been demonstrated consistently to undergo structural and functional alterations in response to DIT. This has been interpreted as a form of defence against a caloric load and also to adjust metabolic rate according to energy availability. Upregulation of UCP-1 content/activity has been shown to be crucial for the ability of the organism to respond to DIT (7). The administration of a nonselective β-blocker (propranolol) prevented the diet-induced increase in V˙O2, indicating that DIT is mediated by increased SNS activity (7). Our recent study indeed showed that feeding rats an HF diet caused a significant increase (∼1.8-fold) in iBAT mass, which was accompanied by significant approximately 2.7- and 1.5-fold increases in UCP-1 content and palmitate oxidation, respectively (34). Conversely, endurance training markedly reduced the content of PGC-1α and UCP-1 in iBAT and aBAT and suppressed FA oxidation in these classical BAT (34). From a physiological perspective, the exercise-induced reduction in the thermogenic capacity of iBAT and aBAT could serve as a mechanism that reduces heat production in core areas of the body and allows the organism to better cope with the regular increase in exercise-derived heat (Fig. 3).

Exercise- and Diet-Induced Alterations in the Thermogenic Capacity of WAT

An interesting observation of our study was that, although both the mass and oxidative capacity of iBAT and aBAT were significantly reduced by endurance training, a pronounced browning of the SC Ing WAT occurred (34). Further microscopic analysis revealed the presence of a reduced number of white adipocytes and a much larger number of multilocular adipocytes in SC Ing fat of endurance-trained than sedentary rats (34). The lipid content of multilocular brownlike adipocytes clearly was reduced in the SC Ing fat of endurance-trained adipocytes, indicating that these cells indeed mobilized their energy stores. Palmitate oxidation in the SC Ing fat depot was enhanced significantly with exercise, an effect that also was accompanied by a marked increase in UCP-1 content in this fat depot when compared with sedentary controls (34). These exercise effects were specific to the SC Ing WAT because UCP-1 could not be detected in visceral fat depots such as the epididymal and retroperitoneal (34). Furthermore, there were specific regions of the SC Ing fat pad that elicited a more pronounced browning response to chronic endurance training. The middle region could be differentiated visually from the proximal and distal extremities of the SC Ing fat depot (34). Adipocytes in the middle region were enriched with UCP-1, and microscopic analysis revealed that these cells had a multilocular appearance. Mean adipocyte area also was higher in the extremities than in the middle region of the SC Ing fat pad. Interestingly, mean adipocyte area did not differ between sedentary animals fed either low-fat (LF) or HF diets (34). This suggests that adipocytes located in the middle region of the rat SC Ing fat pad were resistant to HF-induced hypertrophy, which is compatible with higher thermogenic activity in these cells. These findings provided evidence that not all cells present in the SC WAT respond equally to conditions of energy surplus and deficit. These regional differences in metabolic activity seem to confer great metabolic flexibility to the SC WAT compartment. It does so by allowing the energy surplus to be stored in the form of TG in those adipocytes that are prone to hypertrophy while also regulating its ability to dissipate energy through those cells that have a higher thermogenic capacity. This is compatible with our observations that HF diet reduced UCP-1 content in the SC Ing fat of sedentary animals and significantly attenuated the endurance training-induced increase in UCP-1 in SC Ing fat (34).

A reduction in thermogenic activity in the SC Ing fat depot under conditions of HF feeding allows for the excess lipid ingested to be stored in the WAT, which helps to prevent its accumulation in other peripheral organs such as the heart, liver, and skeletal muscle. Importantly, under sedentary conditions, the SNS simultaneously engages typical BAT in a diet-induced thermogenic response that seems to serve as a mechanism to dissipate energy and counteract the expansion of adiposity (diet-induced thermogenesis), as well as to regulate body weight across time (26). However, under exercising conditions, the organism seems to suppress the thermogenic response triggered by HF feeding in typical BAT located in core areas of the body (34). This likely occurs to allow the organism to cope with the regular exposure to increased heat production caused by endurance training. In this context, the browning effect of exercise on the SC WAT seems to provide a mechanism that allows the organism to mount a diet-induced thermogenic response while reducing heat production by classical BAT located in core areas of the body (Fig. 3). The increase in energy expenditure induced by exercise also facilitates the regulation of adiposity under conditions of energy surplus such as HF feeding. Thus, the energy cost of exercise combined with the browning effect of SC WAT may suffice to limit the expansion of adiposity under conditions of HF feeding, despite reduced thermogenic activity in classical BAT. This is supported by the findings that body mass and adiposity of HF-fed animals exposed to endurance training were similar to those of LF-fed sedentary controls, and that chronic endurance exercise and HF diet-induced obesity exerted antagonistic regulatory effects on thermogenesis in iBAT/aBAT and SC Ing fat depots (34).

An important issue that is often raised refers to whether the exercise-induced browning of the WAT found in rodents also occurs in humans. From the results reported in few humans studies so far, no clear signs of browning have been detected in endurance-trained subjects (19,25). This has been based on the observations that the expression of selected genes considered markers of WAT browning (PRDM16, TBX1, TMEM26, and CD137) did not differ between sedentary and endurance-trained subjects (19,25), although the mRNA expression of UCP-1 in the SC WAT has been reported to be increased in subjects exposed to 12 wk of endurance training (19). Also, these studies were based on single-biopsy mRNA analysis of the SC abdominal (19) and thigh (25) WAT areas and may have missed browning that could have taken place in a site-specific manner within the SC WAT. The exercise-induced browning effect does not seem to take place uniformly throughout the SC WAT. Our data in rats provide evidence that there are specific areas within the SC Ing WAT that undergo browning on exposure to chronic endurance training, whereas others do not (34). If this also is the case in humans, then it may require multiple biopsies from the SC WAT in each subject to find regions where cells possibly undergo browning in response to chronic endurance training. This obviously poses a major limitation to human studies and makes it extremely difficult to determine whether the findings from rodents apply to humans. The use of 18F-fluorodeoxy glucose positron emission tomography/computed tomography scans for the identification of active BAT (6) does not seem to be sensitive enough to detect specific areas within the WAT that might undergo browning. Therefore, perhaps it will not be until novel, less invasive, and highly sensitive methods of studying BAT activity are developed that a definitive answer is provided to whether or not cells within the human SC WAT undergo browning in response to chronic exercise training.

WAT and BAT Plasticity and Its Impact on Whole-Body Energy Homeostasis

The possibility of increasing energy expenditure by inducing a brownlike metabolic phenotype in WAT is of great therapeutic interest. Also, BAT predominantly uses FA as substrate with only a fraction of its total metabolism derived from glucose (4), so even partially or temporally activated BAT could be beneficial for maintaining a healthy metabolic phenotype. However, little is known about how much WAT browning can contribute to alter daily whole-body energy expenditure or substrate partitioning under resting conditions. It has been estimated that as little as 40–50 g of typical BAT could, if maximally stimulated, account for approximately 20% of daily energy expenditure (26). Although potentially significant, this is based on indirect histological and thermographic human data (26), and its applicability to the actual BAT contribution to whole-body energy expenditure should be taken with great caution. Furthermore, it still remains to be determined if the energy-dissipating capacity of white adipocytes undergoing browning is the same as that of typical BAT.

Teasing out the effects of exercise-induced browning of the SC WAT on whole-body energy expenditure is a complex task because exercise itself consumes energy, produces heat, and promotes systemic metabolic alterations that do not cease immediately on its interruption. It has been well documented that energy expenditure remains elevated after exercise cessation, referred to as the excess postexercise O2 consumption (32). In this context, a number of studies have attempted to assess the effects of chronic exercise training on RMR in humans and animals with mixed reported results (32). We have used indirect calorimetry to measure whole-body energy expenditure during the light and dark cycles in sedentary and endurance-trained rats fed either HF or LF diets. Measurements of O2 consumption, RER, and spontaneous physical activity were taken 24 h after the last exercise bout to minimize the potentially confounding effect of acute exercise on these variables (34). We have found that energy expenditure during the dark cycle was increased by 14.2% and 16.8% in LF- and HF-fed endurance-trained rats, respectively, when compared with sedentary LF- and HF-fed controls. This occurred despite significant reductions in thermogenic capacity/activity of classical BAT (iBAT and aBAT) in LF- and HF-fed endurance-trained rats (34). Such findings cannot be attributed solely to exercise-induced browning of the SC Ing fat pad, although it may have contributed at least partially to increase whole-body energy expenditure in chronically endurance-trained rats. Therefore, these findings suggest that browning of the SC WAT compensated for the reduction in thermogenic activity in typical BAT located in core areas of the body and actually raised RMR in rats exposed to chronic endurance training. Importantly, the browning effect found in LF- and HF-fed rats exposed to chronic endurance training also was accompanied by reduced adiposity in these animals when compared with sedentary controls (34). Thus, it is plausible that, besides the increased energy expenditure promoted by the extra work of regular exercise, the mitochondrial uncoupling derived from exercise-induced browning of the SC WAT had an additional contribution to promote a negative energy balance condition that led to reduced adiposity. This could be a potential mechanism to explain why regular exercise often is associated with better outcomes in long-term fat loss and maintenance of a reduced body weight in humans.


Exercise increases energy expenditure and promotes a wide range of beneficial health effects that go well beyond the physiological and metabolic adaptations that occur within skeletal muscles. We are now learning that chronic endurance exercise induces browning of the WAT in a depot-specific manner. This is characterized by increased gene expression and protein content in the SC WAT of UCP-1, a unique marker of brown adipocytes. This also is accompanied by the presence in the SC WAT of a large number of cells displaying multilocular rather than the typical unilocular appearance of white adipocytes. Conversely, mass and thermogenic capacity of classical BAT located in core areas of the body are significantly reduced and become enriched with unilocular adipocytes. This suggests that WAT and BAT are plastic tissues with the ability of acquiring metabolic features of one another. Whether this is caused by transdifferentiation of existing fully mature adipocytes, recruitment of undifferentiated precursor cells that develop into thermogenically competent beige adipocytes, or a combination of both processes still remains under debate.

Endurance exercise seems to shift thermogenesis from core to peripheral areas of the body and does so by engaging specific molecular targets in the SC WAT that are induced typically in classical BAT by activation of the SNS under cold exposure and HF-feeding conditions (Fig. 3). Dissecting the molecular mechanisms by which different physiological conditions (e.g., cold exposure, diet-induced obesity, and endurance exercise training) regulate thermogenesis in the SC WAT is of great relevance for the development of potential therapeutic strategies aimed at promoting energy dissipation in the WAT.

The implications of the antagonistic regulation by endurance training of WAT and BAT thermogenic capacity for whole-body energy expenditure still are not fully understood. However, recent studies suggest that browning of the SC WAT may compensate for the exercise-induced downregulation of classical BAT thermogenic activity and may elevate RMR in rodents. Therefore, plasticity of WAT and BAT confers great metabolic flexibility to these tissues, and we propose that this allows the organism to adjust its metabolic rate and substrate partitioning according to changes in availability and demand for energy under various physiological conditions. In this context, the development of strategies that target the induction of browning of the SC WAT potentially may be useful in the treatment of obesity and its related metabolic disorders.

This research was funded by a Natural Science and Engineering Research Council of Canada Discovery Grant (no. 311818-2011) and infrastructure grants from the Canada Foundation for Innovation and the Ontario Research Fund awarded to R.B. Ceddia. D.M. Sepa-Kishi was supported by the Elia Scholarship and the NSERC Alexander Graham Bell Canada Graduate Doctoral Scholarship.


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brown fat; UCP-1; exercise; beige adipocytes; irisin; AMPK; energy expenditure

© 2016 American College of Sports Medicine