Commentaries to Accompany
The role of brown adipose tissue (BAT) in defending body temperature was demonstrated initially by Foster and Frydman (1) who showed that BAT was the site of cold-induced thermogenesis. This was followed by the identification that heat production occurred via the uncoupling of BAT mitochondria through uncoupling protein 1 (UCP1) (5). Finally, work from Flier and colleagues demonstrated that BAT protected mice against the development of obesity and diabetes (2) and firmly established BAT as a thermoregulatory organ that could be targeted to reduce the risk of obesity and diabetes. Around the same time it was suggested that BAT could actively defend body weight through diet-induced thermogenesis (DIT). More recently, the discovery of BAT in adult humans has renewed interest in brown fat research and in understanding ways to remodel white adipose tissue (WAT) to a phenotype more similar to BAT. This process, termed “browning,” is marked by the appearance of “beige” adipocytes in WAT that are functionally similar to brown adipocytes. Exercise had been postulated for a while to reduce BAT thermogenesis, but, somewhat surprisingly, recent work has demonstrated that endurance training promotes the browning of WAT in rodents. At first glance, exercise-induced browning of WAT seems somewhat counterintuitive; however, in the current issue of the Journal, Sepa-Kishi and Ceddia (6) discuss novel findings that might explain the opposing effects of exercise on BAT and subcutaneous WAT (scWAT) thermogenesis.
Sepa-Kishi and Ceddia (6) put forth the hypothesis that remodeling of adipose tissue during exercise training functions to shift thermogenesis away from classical BAT toward scWAT, where it would not necessarily affect core body temperature. In effect, this would allow the animal to deal with greater heat production during exercise. These ideas stem from their recent study in which endurance training reduced UCP1 content and lipid oxidation in classical BAT. In contrast, exercise promoted beige adipocytes, UCP1 content, and fatty acid oxidation in scWAT. An interesting observation was that energy expenditure after exercise remained elevated despite a reduction in BAT thermogenesis, leading the authors to suggest that exercise-induced scWAT browning can compensate partially for the reduction in BAT. Similarly, scWAT browning could limit adiposity during high-fat feeding by promoting DIT.
The beneficial effects of exercise on whole-body energy homeostasis are undoubtable, but the exact contribution of scWAT browning and the reality of DIT are a matter of debate (3). Indeed, exercise does suppress BAT activity in humans; however, the evidence for browning is less apparent (7). Alternatively, the reduction in BAT activity could be a means of shifting energy away from uncoupling and toward working muscle, whereas the increase in WAT fatty acid oxidation might partly support adenosine triphosphate synthesis required for greater in situ de novo lipogenesis (4). Exercise training at thermoneutrality or in UCP1 knockout mice could be useful in teasing apart UCP1-dependent versus -independent effects on whole-body energy expenditure. In addition, as stated by the authors, understanding the cellular source of beige cells and the neural circuitry involved in the downregulation of BAT and upregulation of scWAT browning could prove useful in discovering novel therapies to combat obesity and diabetes.
Emilio P. Mottillo
Department of Medicine
Hamilton, Ontario, Canada
1. Foster DO, Frydman ML. Nonshivering thermogenesis in the rat. II. Measurements of blood flow with microspheres point to brown adipose tissue as the dominant site of the calorigenesis induced by noradrenaline. Can. J. Physiol. Pharmacol.
1978; 56( 1): 110–22.
2. Hamann A, Benecke H, Le Marchand-Brustel Y, Susulic VS, Lowell BB, Flier JS. Characterization of insulin resistance and NIDDM in transgenic mice with reduced brown fat. Diabetes
. 1995; 44( 11): 1266–73.
3. Kozak LP. Brown fat and the myth of diet-induced thermogenesis. Cell Metab.
2010; 11( 4): 263–7.
4. Mottillo EP, Balasubramanian P, Lee YH, Weng C, Kershaw EE, Granneman JG. Coupling of lipolysis and de novo
lipogenesis in brown, beige, and white adipose tissues during chronic β3-adrenergic receptor activation. J. Lipid Res.
2014; 55( 11): 2276–86.
5. Nicholls DG, Locke RM. Thermogenic mechanisms in brown fat. Physiol. Rev.
1984; 64( 1): 1–64.
6. Sepa-Kishi DM, Ceddia RB. Exercise-mediated effects on white and brown adipose tissue plasticity and metabolism. Exerc. Sport Sci. Rev.
2015; 44: 37–44.
7. Vosselman MJ, Hoeks J, Brans B, et al. Low brown adipose tissue activity in endurance-trained compared with lean sedentary men. Int. J. Obes. (Lond.)
. 2015; doi: 10.1038/ijo.2015.130.