Adaptive thermogenesis, defined as the heat produced in response to environmental temperature or diet, can be divided into three subtypes. Cold exposure induces shivering thermogenesis, a function of skeletal muscle, and non-shivering thermogenesis, a function of brown fat. Overfeeding triggers diet-induced thermogenesis; this is also a function of brown fat.
Recent studies using positron emission tomography (PET) and computed tomography (CT) imaging prove that adult humans possess physiologically active uncoupled protein 1 (UCP1)-positive brown fat, leading to the consideration within the medical and scientific communities that brown fat may play a part in normal physiology and could be a target for obesity treatment.
There are at least two types of brown fat cells located in different anatomical locations in mice, each arising from different developmental origins. Compared with the preformed interscapular brown fat cells, the systemic brown fat cells, found in white fat and between muscle bundles, are often found admixed with white adipocytes; are more sensitive to β3-adrenergic receptor stimulation and cold exposure; and have a thermogenic capacity that seems to be regulated by genetic background. The contribution of the two different populations of progenitors to adult human brown fat remains to be determined.
Three types of thermogenesis occur in skeletal muscle: exercise-induced thermogenesis, non-exercise activity thermogenesis, and cold-induced shivering thermogenesis. Thus, therapeutic interventions that mimic these mechanisms could potentially increase the thermogenic capacity of muscle and counteract obesity. This is especially beneficial to individuals with physical limitations in exercising or to those who are genetically predisposed to obesity.
Based on the current knowledge of bioenergetics, four potential therapeutic approaches could be envisioned: increasing brown fat differentiation from progenitor cells; activating brown fat thermogenesis; promoting skeletal muscle thermogenesis; or increasing general mitochondrial uncoupling.
Obesity develops when energy intake exceeds energy expenditure. Although most current obesity therapies are focused on reducing calorific intake, recent data suggest that increasing cellular energy expenditure (bioenergetics) may be an attractive alternative approach. This is especially true for adaptive thermogenesis — the physiological process whereby energy is dissipated in mitochondria of brown fat and skeletal muscle in the form of heat in response to external stimuli. There have been significant recent advances in identifying the factors that control the development and function of these tissues, and in techniques to measure brown fat in human adults. In this article, we integrate these developments in relation to the classical understandings of cellular bioenergetics to explore the potential for developing novel anti-obesity therapies that target cellular energy expenditure.
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Haslam, D. W. & James, W. P. Obesity. Lancet 366, 1197–1209 (2005).
Rolfe, D. F. & Brown, G. C. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol. Rev. 77, 731–758 (1997).
Lowell, B. B. & Spiegelman, B. M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652–660 (2000).
Wing, R. R. & Phelan, S. Long-term weight loss maintenance. Am. J. Clin. Nutr. 82, 222S–225S (2005).
Kaplan, L. M. Pharmacological therapies for obesity. Gastroenterol. Clin. North Am. 34, 91–104 (2005).
Welle, S., Forbes, G. B., Statt, M., Barnard, R. R. & Amatruda, J. M. Energy expenditure under free-living conditions in normal-weight and overweight women. Am. J. Clin. Nutr. 55, 14–21 (1992).
Melnikova, I. & Wages, D. Anti-obesity therapies. Nature Rev. Drug Discov. 5, 369–370 (2006).
Wells, J. C. Thrift: a guide to thrifty genes, thrifty phenotypes and thrifty norms. Int. J. Obes. (Lond.) 33, 1331–1318 (2009).
Speakman, J. R. A nonadaptive scenario explaining the genetic predisposition to obesity: the “predation release” hypothesis. Cell. Metab. 6, 5–12 (2007).
Padwal, R. S. & Majumdar, S. R. Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet 369, 71–77 (2007).
Redman, L. M. et al. Metabolic and behavioral compensations in response to caloric restriction: implications for the maintenance of weight loss. PLoS ONE 4, e4377 (2009).
Leibel, R. L., Rosenbaum, M. & Hirsch, J. Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med. 332, 621–628 (1995). This paper demonstrates that changes in body weight by diet are associated with compensatory changes in energy expenditure, which may account for the poor long-term efficacy of treatments for obesity.
Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).
Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).
Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).
Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526–1531 (2009).
Zingaretti, M. C. et al. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J. 23, 3113–3120 (2009). References 13–17 report the rediscovery of metabolically active brown fat in adult humans using non-invasive PET and CT scans coupled with immunohistochemistry, electron microscopy, and gene and protein expression assays. These led to the consideration that brown fat may play a role in normal physiology and could be a target for obesity treatment.
Harper, M. E., Green, K. & Brand, M. D. The efficiency of cellular energy transduction and its implications for obesity. Annu. Rev. Nutr. 28, 13–33 (2008). This comprehensive review discusses bioenergetics and the reasons for targeting uncoupling for the treatment of obesity.
Gosselin, C. & Cote, G. Weight loss maintenance in women two to eleven years after participating in a commercial program: a survey. BMC Womens Health 1, 2 (2001).
Tam, J., Fukumura, D. & Jain, R. K. A mathematical model of murine metabolic regulation by leptin: energy balance and defense of a stable body weight. Cell. Metab. 9, 52–63 (2009).
Chow, C. C. & Hall, K. D. The dynamics of human body weight change. PLoS Comput. Biol. 4, e1000045 (2008).
Green, D. E. & Zande, H. D. Universal energy principle of biological systems and the unity of bioenergetics. Proc. Natl Acad. Sci. USA 78, 5344–5347 (1981).
Clapham, J. C. & Arch., J. R. Thermogenic and metabolic antiobesity drugs: rationale and opportunities. Diabetes Obes. Metab. 9, 259–275 (2007).
Randle, P. J., Garland, P. B., Hales, C. N. & Newsholme, F. A. The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1, 785–789 (1963).
Newsholme, E. A. & Crabtree, B. Substrate cycles in metabolic regulation and in heat generation. Biochem. Soc. Symp. 61–109 (1976).
Wolfe, R. R., Herndon, D. N., Jahoor, F., Miyoshi, H. & Wolfe, M. Effect of severe burn injury on substrate cycling by glucose and fatty acids. N. Engl. J. Med. 317, 403–408 (1987).
Klein, S. & Wolfe, R. R. Whole-body lipolysis and triglyceride-fatty acid cycling in cachectic patients with esophageal cancer. J. Clin. Invest. 86, 1403–1408 (1990).
Wolfe, R. R., Klein, S., Carraro, F. & Weber, J. M. Role of triglyceride–fatty acid cycle in controlling fat metabolism in humans during and after exercise. Am. J. Physiol. 258, E382–E389 (1990).
Mazzucotelli, A. et al. The transcriptional coactivator peroxisome proliferator activated receptor (PPAR)γ coactivator-1α and the nuclear receptor PPARα control the expression of glycerol kinase and metabolism genes independently of PPARγ activation in human white adipocytes. Diabetes 56, 2467–2475 (2007).
Golozoubova, V. et al. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J. 15, 2048–2050 (2001).
Enerback, S. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–94 (1997).
Kontani, Y. et al. UCP1 deficiency increases susceptibility to diet-induced obesity with age. Aging Cell 4, 147–155 (2005).
Feldmann, H. M., Golozoubova, V., Cannon, B. & Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell. Metab. 9, 203–209 (2009). This paper demonstrates that diet-induced thermogenesis is fully dependent on UCP1, thus Ucp1 -knockout mice exhibit increased susceptibility to diet-induced obesity when kept at thermoneutrality.
Kopecky, J., Clarke, G., Enerback, S., Spiegelman, B. & Kozak, L. P. Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J. Clin. Invest. 96, 2914–2923 (1995).
Leonardsson, G. et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc. Natl Acad. Sci. USA 101, 8437–8442 (2004).
Foster, D. O. & Frydman, M. L. Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow: the dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis. Can. J. Physiol. Pharmacol. 57, 257–270 (1979).
Mifflin, M. D. et al. A new predictive equation for resting energy expenditure in healthy individuals. Am. J. Clin. Nutr. 51, 241–247 (1990).
Rothwell, N. J. & Stock, M. J. Luxuskonsumption, diet-induced thermogenesis and brown fat: the case in favour. Clin. Sci. (Lond.) 64, 19–23 (1983).
Bouchard, C. et al. The response to long-term overfeeding in identical twins. N. Engl. J. Med. 322, 1477–1482 (1990). This study suggests that genetic factors play a major role for the variations in weight gain in response to overfeeding.
Maes, H. H., Neale, M. C. & Eaves, L. J. Genetic and environmental factors in relative body weight and human adiposity. Behav. Genet. 27, 325–351 (1997).
Christiansen, E., Garby, L. & Sorensen, T. I. Quantitative analysis of the energy requirements for development of obesity. J. Theor. Biol. 234, 99–106 (2005).
[No authors listed]. Human energy requirements: report of a joint FAO/WHO/UNU expert consultation. Food. Nutr. Bull. 26, 166 (2005).
Levine, J. A. Nonexercise activity thermogenesis — liberating the life-force. J. Intern. Med. 262, 273–287 (2007).
Stowell, K. M. Malignant hyperthermia: a pharmacogenetic disorder. Pharmacogenomics 9, 1657–1672 (2008).
Wijers, S. L., Schrauwen, P., Saris, W. H. & Marken Lichtenbelt, W. D. Human skeletal muscle mitochondrial uncoupling is associated with cold induced adaptive thermogenesis. PLoS ONE 3, e1777 (2008).
Himms-Hagen, J. Exercise in a pill: feasibility of energy expenditure targets. Curr. Drug Targets CNS Neurol. Disord. 3, 389–409 (2004).
Lean, M. E., James, W. P., Jennings, G. & Trayhurn, P. Brown adipose tissue uncoupling protein content in human infants, children and adults. Clin. Sci. (Lond.) 71, 291–297 (1986).
Neumann, R. O. Experimentelle Beitrage Zur Lehre von den taglichen Nahrungsbedarf des Menschen unter besonderer Bernuksichtigung der notwendigen Eiweissmenge. Archiv fur Hygeine 45, 1–87 (1902) (in German).
Rothwell, N. J. & Stock, M. J. A role for brown adipose tissue in diet-induced thermogenesis. Nature 281, 31–35 (1979). This paper establishes the importance of diet-induced thermogenesis via the function of brown fat in energy balance, and suggests that BAT plays a key part in metabolic efficiency and resistance to obesity.
Trayhurn, P., Thurlby, P. L. & James, W. P. Thermogenic defect in pre-obese ob/ob mice. Nature 266, 60–62 (1977).
Trayhurn, P., Goodbody, A. E. & James, W. P. A role for brown adipose tissue in the genesis of obesity? Studies on experimental animals. Proc. Nutr. Soc. 41, 127–131 (1982).
Mercer, S. W. & Trayhurn, P. Effect of high fat diets on energy balance and thermogenesis in brown adipose tissue of lean and genetically obese ob/ob mice. J. Nutr. 117, 2147–2153 (1987).
Wijers, S. L., Saris, W. H. & Marken Lichtenbelt, W. D. Individual thermogenic responses to mild cold and overfeeding are closely related. J. Clin. Endocrinol. Metab. 92, 4299–4305 (2007).
Hosaka, T. et al. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc. Natl Acad. Sci. USA 101, 2975–2980 (2004).
Nakamura, K. & Morrison, S. F. Central efferent pathways mediating skin cooling-evoked sympathetic thermogenesis in brown adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R127–R136 (2007).
Morrison, S. F., Nakamura, K. & Madden, C. J. Central control of thermogenesis in mammals. Exp. Physiol. 93, 773–797 (2008).
Nakamura, K. & Morrison, S. F. A thermosensory pathway that controls body temperature. Nature Neurosci. 11, 62–71 (2008).
Zhang, Y. H., Yanase-Fujiwara, M., Hosono, T. & Kanosue, K. Warm and cold signals from the preoptic area: which contribute more to the control of shivering in rats? J. Physiol. 485, 195–202 (1995).
Tanaka, M., Owens, N. C., Nagashima, K., Kanosue, K. & McAllen, R. M. Reflex activation of rat fusimotor neurons by body surface cooling, and its dependence on the medullary raphe. J. Physiol. 572, 569–583 (2006).
Brown, J. W., Sirlin, E. A., Benoit, A. M., Hoffman, J. M. & Darnall, R. A. Activation of 5-HT1A receptors in medullary raphe disrupts sleep and decreases shivering during cooling in the conscious piglet. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R884–R894 (2008).
Vybiral, S., Lesna, I., Jansky, L. & Zeman, V. Thermoregulation in winter swimmers and physiological significance of human catecholamine thermogenesis. Exp. Physiol. 85, 321–326 (2000).
van Ooijen, A. M., Marken Lichtenbelt, W. D., van Steenhoven, A. A. & Westerterp, K. R. Cold-induced heat production preceding shivering. Br. J. Nutr. 93, 387–391 (2005).
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
Golozoubova, V. et al. Depressed thermogenesis but competent brown adipose tissue recruitment in mice devoid of all hormone-binding thyroid hormone receptors. Mol. Endocrinol. 18, 384–401 (2004).
Silva, J. E. Thermogenic mechanisms and their hormonal regulation. Physiol. Rev. 86, 435–464 (2006).
Mistry, A. M., Swick, A. G. & Romsos, D. R. Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice. J. Nutr. 127, 2065–2072 (1997).
Commins, S. P. et al. Norepinephrine is required for leptin effects on gene expression in brown and white adipose tissue. Endocrinology 140, 4772–4778 (1999).
Elmquist, J. K., Maratos-Flier, E., Saper, C. B. & Flier, J. S. Unraveling the central nervous system pathways underlying responses to leptin. Nature Neurosci. 1, 445–449 (1998).
Harris, R. B. Leptin — much more than a satiety signal. Annu. Rev. Nutr. 20, 45–75 (2000).
Rosenbaum, M. et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J. Clin. Invest. 115, 3579–3586 (2005).
Ferrannini, E. et al. Insulin: new roles for an ancient hormone. Eur. J. Clin. Invest. 29, 842–852 (1999).
Weyer, C., Bogardus, C., Mott, D. M. & Pratley, R. E. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J. Clin. Invest. 104, 787–794 (1999).
Ghorbani, M., Claus, T. H. & Himms-Hagen, J. Hypertrophy of brown adipocytes in brown and white adipose tissues and reversal of diet-induced obesity in rats treated with a β3-adrenoceptor agonist. Biochem. Pharmacol. 54, 121–131 (1997).
Guerra, C., Koza, R. A., Yamashita, H., Walsh, K. & Kozak, L. P. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J. Clin. Invest. 102, 412–420 (1998). This paper reports that genetic backgrounds affect the emergence of brown adipocytes within white fat in response to β 3 -adrenergic receptor stimulation.
Lowell, B. B. et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366, 740–742 (1993). This study uses a transgenic toxigene approach to ablate BAT in mice, and demonstrates that brown fat deficiency leads to increased metabolic efficiency and obesity.
Heaton, J. M. The distribution of brown adipose tissue in the human. J. Anat. 112, 35–39 (1972).
Astrup, A. Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation. Acta Endocrinol. Suppl. (Copenh.) 278, 1–32 (1986).
Weyer, C., Tataranni, P. A., Snitker, S., Danforth, E. Jr & Ravussin, E. Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective β3-adrenoceptor agonist in humans. Diabetes 47, 1555–1561 (1998).
Larsen, T. M. et al. Effect of a 28-d treatment with L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am. J. Clin. Nutr. 76, 780–788 (2002).
Cunningham, S. et al. The characterization and energetic potential of brown adipose tissue in man. Clin. Sci. (Lond.) 69, 343–348 (1985).
Nedergaard, J., Bengtsson, T. & Cannon, B. Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444–E452 (2007).
Schoder, H., Larson, S. M. & Yeung, H. W. PET/CT in oncology: integration into clinical management of lymphoma, melanoma, and gastrointestinal malignancies. J. Nucl. Med. 45 (Suppl. 1), 72–81 (2004).
Hany, T. F. et al. Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur. J. Nucl. Med. Mol. Imaging 29, 1393–1398 (2002).
Cohade, C., Osman, M., Pannu, H. K. & Wahl, R. L. Uptake in supraclavicular area fat (“USA-Fat”): description on 18F-FDG PET/CT. J. Nucl. Med. 44, 170–176 (2003). References 81, 83 and 84 suggest that brown fat can be visualized in adult humans by PET and CT scans.
Ravussin, E. & Kozak, L. P. Have we entered the brown adipose tissue renaissance? Obes. Rev. 10, 265–268 (2009).
Almind, K., Manieri, M., Sivitz, W. I., Cinti, S. & Kahn, C. R. Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice. Proc. Natl Acad. Sci. USA 104, 2366–2371 (2007).
Xue, B. et al. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J. Lipid Res. 48, 41–51 (2007).
Cohade, C., Mourtzikos, K. A. & Wahl, R. L. “USA-Fat”: prevalence is related to ambient outdoor temperature-evaluation with 18F-FDG PET/CT. J. Nucl. Med. 44, 1267–1270 (2003).
Gesta, S., Tseng, Y. H. & Kahn, C. R. Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007).
Atit, R. et al. β-Catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev. Biol. 296, 164–176 (2006).
Timmons, J. A. et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc. Natl Acad. Sci. USA 104, 4401–4406 (2007).
Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008). References 90–92 demonstrate a common developmental ancestry for interscapular brown fat and skeletal muscle in mice.
Petrovic, N. et al. Chronic peroxisome proliferator-activated receptor γ (PPARγ) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classical brown adipocytes. J. Biol. Chem. 285, 7153–7164 (2010).
Cinti, S. Transdifferentiation properties of adipocytes in the adipose organ. Am. J. Physiol. Endocrinol. Metab. 297, E977–E986 (2009).
Fink, B. D. et al. Mitochondrial proton leak in obesity-resistant and obesity-prone mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1773–R1780 (2007).
Lean, M. E. J. & James, W. P. T. in Brown Adipose Tissue (eds Trayhurn, P. & Nicholls, D. G.) 339–365 (Edward Arnold, London, 1986).
Choy, L. & Derynck, R. Transforming growth factor-β inhibits adipocyte differentiation by Smad3 interacting with CCAAT/enhancer-binding protein (C/EBP) and repressing C/EBP transactivation function. J. Biol. Chem. 278, 9609–9619 (2003).
Alessi, M. C. et al. Plasminogen activator inhibitor 1, transforming growth factor-β1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 49, 1374–1380 (2000).
Samad, F., Yamamoto, K., Pandey, M. & Loskutoff, D. J. Elevated expression of transforming growth factor-β in adipose tissue from obese mice. Mol. Med. 3, 37–48 (1997).
Schulz, T. J. & Tseng, Y. H. Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Cytokine. Growth Factor Rev. 20, 523–531 (2009).
Tseng, Y. H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008). This paper identifies BMP7 as an inducer of brown adipocyte differentiation, and demonstrates that adenoviral-mediated expression of BMP7 in mice leads to increased brown fat-mediated energy expenditure and reduced weight gain.
Shen, J. J. et al. Deficiency of growth differentiation factor 3 protects against diet-induced obesity by selectively acting on white adipose. Mol. Endocrinol. 23, 113–123 (2009).
Yamashita, H. et al. Basic fibroblast growth factor (bFGF) contributes to the enlargement of brown adipose tissue during cold acclimation. Pflugers Arch. 428, 352–356 (1994).
Konishi, M., Mikami, T., Yamasaki, M., Miyake, A. & Itoh, N. Fibroblast growth factor-16 is a growth factor for embryonic brown adipocytes. J. Biol. Chem. 275, 12119–12122 (2000).
Tomlinson, E. et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143, 1741–1747 (2002).
Badman, M. K. et al. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell. Metab. 5, 426–437 (2007).
Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005).
Mori, K. et al. Disruption of klotho gene causes an abnormal energy homeostasis in mice. Biochem. Biophys. Res. Commun. 278, 665–670 (2000).
Tseng, Y. H., Kriauciunas, K. M., Kokkotou, E. & Kahn, C. R. Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol. Cell Biol. 24, 1918–1929 (2004).
Fasshauer, M. et al. Essential role of insulin receptor substrate-2 in insulin stimulation of glut4 translocation and glucose uptake in brown adipocytes. J. Biol. Chem. 275, 25494–25501 (2000).
Tseng, Y. H., Ueki, K., Kriauciunas, K. M. & Kahn, C. R. Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. J. Biol. Chem. 277, 31601–31611 (2002).
Levine, J. A., Eberhardt, N. L. & Jensen, M. D. Role of nonexercise activity thermogenesis in resistance to fat gain in humans. Science 283, 212–214 (1999). This paper suggests the importance of non-exercise activity thermogenesis in dissipating excess energy to preserve leanness in humans.
Badjatia, N. et al. Predictors and clinical implications of shivering during therapeutic normothermia. Neurocrit. Care 6, 186–191 (2007).
Goodyear, L. J. The exercise pill — too good to be true? N. Engl. J. Med. 359, 1842–1844 (2008).
Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).
Lin, J. et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418, 797–801 (2002).
Arruda, A. P. et al. Cold tolerance in hypothyroid rabbits: role of skeletal muscle mitochondria and sarcoplasmic reticulum Ca2+ ATPase isoform 1 heat production. Endocrinology 149, 6262–6271 (2008).
Nelson, D. L. & Gehlert, D. R. Central nervous system biogenic amine targets for control of appetite and energy expenditure. Endocrine 29, 49–60 (2006).
Astrup, A., Bulow, J., Madsen, J. & Christensen, N. J. Contribution of BAT and skeletal muscle to thermogenesis induced by ephedrine in man. Am. J. Physiol. 248, E507–E515 (1985).
Elabd, C. et al. Human multipotent adipose-derived stem cells differentiate into functional brown adipocytes. Stem Cells 27, 2753–2760 (2009).
Crisan, M. et al. A reservoir of brown adipocyte progenitors in human skeletal muscle. Stem Cells 26, 2425–2433 (2008).
Tobin, J. F. & Celeste, A. J. Bone morphogenetic proteins and growth differentiation factors as drug targets in cardiovascular and metabolic disease. Drug Discov. Today 11, 405–411 (2006).
Li, T., Surendran, K., Zawaideh, M. A., Mathew, S. & Hruska, K. A. Bone morphogenetic protein 7: a novel treatment for chronic renal and bone disease. Curr. Opin. Nephrol. Hypertens. 13, 417–422 (2004).
Wang, S. et al. Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int. 63, 2037–2049 (2003).
Chou, J. et al. Neuroregenerative effects of BMP7 after stroke in rats. J. Neurol. Sci. 240, 21–29 (2006).
Harvey, B. K. et al. Neurotrophic effects of bone morphogenetic protein-7 in a rat model of Parkinson's disease. Brain Res. 1022, 88–95 (2004).
Zuch, C. L. et al. Beneficial effects of intraventricularly administered BMP-7 following a striatal 6-hydroxydopamine lesion. Brain Res. 1010, 10–16 (2004).
Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Med. 13, 952–961 (2007).
Sugimoto, H. et al. BMP-7 functions as a novel hormone to facilitate liver regeneration. FASEB J. 21, 256–264 (2007).
Beenken, A. & Mohammadi, M. The FGF family: biology, pathophysiology and therapy. Nature Rev. Drug Discov. 8, 235–253 (2009).
Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell. Metab. 6, 38–54 (2007).
Hansen, J. B. et al. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc. Natl Acad. Sci. USA 101, 4112–4117 (2004).
Tseng, Y. H. et al. Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin. Nature Cell Biol. 7, 601–611 (2005).
Shekelle, P. G. et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA 289, 1537–1545 (2003).
Baba, S. et al. Effect of nicotine and ephedrine on the accumulation of 18F-FDG in brown adipose tissue. J. Nucl. Med. 48, 981–986 (2007).
Magkos, F. & Kavouras, S. A. Caffeine use in sports, pharmacokinetics in man, and cellular mechanisms of action. Crit. Rev. Food. Sci. Nutr. 45, 535–562 (2005).
Huang, Z. L. et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nature Neurosci. 8, 858–859 (2005).
Dhar, R. et al. Cardiovascular toxicities of performance-enhancing substances in sports. Mayo Clin. Proc. 80, 1307–1315 (2005).
Boozer, C. N. et al. Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int. J. Obes. Relat Metab. Disord. 26, 593–604 (2002).
De Matteis, R. et al. Immunohistochemical identification of the β3-adrenoceptor in intact human adipocytes and ventricular myocardium: effect of obesity and treatment with ephedrine and caffeine. Int. J. Obes. Relat Metab. Disord. 26, 1442–1450 (2002).
Arch., J. R. The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspectives from β3-adrenoceptor agonists. Naunyn Schmiedebergs. Arch. Pharmacol. 378, 225–240 (2008). This review addresses the effects of leptin on weight loss, and gives a comprehensive discussion of the attempts to develop β 3 -adrenergic receptor agonists to treat obesity.
van Baak, M. A. et al. Acute effect of L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure in obese men. Clin. Pharmacol. Ther. 71, 272–279 (2002).
Colman, E. Dinitrophenol and obesity: an early twentieth-century regulatory dilemma. Regul. Toxicol. Pharmacol. 48, 115–117 (2007).
Baxter, J. D. & Webb, P. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nature Rev. Drug Discov. 8, 308–320 (2009).
Villicev, C. M. et al. Thyroid hormone receptor beta-specific agonist GC-1 increases energy expenditure and prevents fat-mass accumulation in rats. J. Endocrinology 193, 21–29 (2007).
Bryzgalova, G. et al. Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor β subtype selective agonist KB-141. J. Steroid Biochem. Mol. Biol. 111, 262–267 (2008).
Watanabe, M. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484–489 (2006).
Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell. Metab. 10, 167–177 (2009). This paper reports that the compound INT-777, a selective agonist of the TGR5 receptor, induces intestinal GLP1 release and leads to improved liver and pancreatic function.
Tiwari, A. & Maiti, P. TGR5: an emerging bile acid G-protein-coupled receptor target for the potential treatment of metabolic disorders. Drug Discov. Today 14, 523–530 (2009).
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
Friedman, J. M. Leptin at 14 y of age: an ongoing story. Am. J. Clin. Nutr. 89, 973S–979S (2009).
Bluher, S. & Mantzoros, C. S. Leptin in humans: lessons from translational research. Am. J. Clin. Nutr. 89, 991S–997S (2009).
Welt, C. K. et al. Recombinant human leptin in women with hypothalamic amenorrhea. N. Engl. J. Med. 351, 987–997 (2004).
Roth, J. D. et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc. Natl Acad. Sci. USA 105, 7257–7262 (2008).
Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).
Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006).
Yamamoto, H., Schoonjans, K. & Auwerx, J. Sirtuin functions in health and disease. Mol. Endocrinol. 21, 1745–1755 (2007).
Feige, J. N. et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell. Metab. 8, 347–358 (2008).
Koh, H. J., Brandauer, J. & Goodyear, L. J. LKB1 and AMPK and the regulation of skeletal muscle metabolism. Curr. Opin. Clin. Nutr. Metab. Care 11, 227–232 (2008).
Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).
Narkar, V. A. et al. AMPK and PPARδ agonists are exercise mimetics. Cell 134, 405–415 (2008).
Ruderman, N. B., Saha, A. K. & Kraegen, E. W. Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology 144, 5166–5171 (2003).
Guigas, B. et al. Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators. IUBMB Life 61, 18–26 (2009).
Lou, P. H. et al. Mitochondrial uncouplers with an extraordinary dynamic range. Biochem. J. 407, 129–140 (2007).
Rosen, E. D. & MacDougald, O. A. Adipocyte differentiation from the inside out. Nature Rev. Mol. Cell Biol. 7, 885–896 (2006).
Hansen, J. B. & Kristiansen, K. Regulatory circuits controlling white versus brown adipocyte differentiation. Biochem. J. 398, 153–168 (2006).
Farmer, S. R. Molecular determinants of brown adipocyte formation and function. Genes. Dev. 22, 1269–1275 (2008).
Scime, A. et al. Rb and p107 regulate preadipocyte differentiation into white versus brown fat through repression of PGC-1α. Cell. Metab. 2, 283–295 (2005).
Kiskinis, E. et al. RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes. EMBO J. 26, 4831–4840 (2007).
Powelka, A. M. et al. Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. J. Clin. Invest. 116, 125–136 (2006).
Kajimura, S. et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes. Dev. 22, 1397–1409 (2008).
Kajimura, S. et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-β transcriptional complex. Nature 460, 1154-1158 (2009).
Chiu, Y. H., Lee, T. H. & Shen, W. W. Use of low-dose topiramate in substance use disorder and bodyweight control. Psychiatry Clin. Neurosci. 61, 630–633 (2007).
Gadde, K. M., Franciscy, D. M., Wagner, H. R. & Krishnan, K. R. Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA 289, 1820–1825 (2003).
Musi, N. & Goodyear, L. J. Insulin resistance and improvements in signal transduction. Endocrine 29, 73–80 (2006).
English, P. J. et al. Metformin prolongs the postprandial fall in plasma ghrelin concentrations in type 2 diabetes. Diabetes Metab. Res. Rev. 23, 299–303 (2007).
Ahima, R. S. et al. Appetite suppression and weight reduction by a centrally active aminosterol. Diabetes 51, 2099–2104 (2002).
Sowers, J. R. Endocrine functions of adipose tissue: focus on adiponectin. Clin. Cornerstone 9, 32–38 (2008).
Bays, H. E. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes. Res. 12, 1197–1211 (2004).
Ravussin, E. et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring) 17, 1736–1743 (2009).
Remesar, X. et al. Oral oleoyl-estrone induces the rapid loss of body fat in Zucker lean rats fed a hyperlipidic diet. Int. J. Obes. Relat. Metab. Disord. 24, 1405–1412 (2000).
McCarthy, A. A. When enough is too much: new strategies to treat obesity. Chem. Biol. 11, 1025–1026 (2004).
Chaudhri, O. B., Wynne, K. & Bloom, S. R. Can gut hormones control appetite and prevent obesity? Diabetes Care 31 (Suppl. 2), 284–289 (2008).
Glazer, G. Long-term pharmacotherapy of obesity 2000: a review of efficacy and safety. Arch. Intern. Med. 161, 1814–1824 (2001).
Hansen, R. A., Gartlehner, G., Lohr, K. N. & Kaufer, D. I. Functional outcomes of drug treatment in Alzheimer's disease: a systematic review and meta-analysis. Drugs Aging 24, 155–167 (2007).
Astrup, A. et al. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet 372, 1906–1913 (2008).
Appolinario, J. C., Bueno, J. R. & Coutinho, W. Psychotropic drugs in the treatment of obesity: what promise? CNS Drugs 18, 629–651 (2004).
Dwoskin, L. P., Rauhut, A. S., King-Pospisil, K. A. & Bardo, M. T. Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Rev. 12, 178–207 (2006).
Chandra, R. & Liddle, R. A. Cholecystokinin. Curr. Opin. Endocrinol. Diabetes Obes. 14, 63–67 (2007).
Smith, S. R. et al. Lorcaserin (APD356), a selective 5-HT2C agonist, reduces body weight in obese men and women. Obesity (Silver Spring) 17, 494–503 (2009).
Van der Ploeg, L. H. et al. Design and synthesis of (ant)-agonists that alter appetite and adiposity. Prog. Brain Res. 153, 107–118 (2006).
Adan, R. A. et al. The MC4 receptor and control of appetite. Br. J. Pharmacol. 149, 815–827 (2006).
Barak, N., Greenway, F. L., Fujioka, K., Aronne, L. J. & Kushner, R. F. Effect of histaminergic manipulation on weight in obese adults: a randomized placebo controlled trial. Int. J. Obes. (Lond.) 32, 1559–1565 (2008).
Greenway, F. L. et al. Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring) 17, 30–39 (2009).
Li, J. et al. In vitro and in vivo profile of 5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), a novel potent MTP inhibitor for obesity. Bioorg. Med. Chem. Lett. 17, 1996–1999 (2007).
Idris, I. & Donnelly, R. Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diabetes Obes. Metab. 11, 79–88 (2009).
Carlson, M. J. & Cummings, D. E. Prospects for an anti-ghrelin vaccine to treat obesity. Mol. Interv. 6, 249–252 (2006).
Morton, N. M. & Seckl, J. R. 11β-hydroxysteroid dehydrogenase type 1 and obesity. Front. Horm. Res. 36, 146–164 (2008).
Hartman, M. L. et al. Growth hormone replacement therapy in adults with growth hormone deficiency improves maximal oxygen consumption independently of dosing regimen or physical activity. J. Clin. Endocrinol. Metab. 93, 125–130 (2008).
Ruderman, N. B. et al. AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise. Acta Physiol. Scand. 178, 435–442 (2003).
Ahmadian, M. et al. Adipose overexpression of desnutrin promotes fatty acid use and attenuates diet-induced obesity. Diabetes 58, 855–866 (2009).
Kok, P. et al. Activation of dopamine D2 receptors simultaneously ameliorates various metabolic features of obese women. Am. J. Physiol. Endocrinol. Metab. 291, E1038–E1043 (2006).
Wang, Y. X. et al. Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell 113, 159–170 (2003).
Buckley, J. D. & Howe, P. R. Anti-obesity effects of long-chain omega-3 polyunsaturated fatty acids. Obes. Rev. 10, 648–659 (2009).
We thank L. J. Goodyear for critical reading of the manuscript. This work was supported in part by National Institutes of Health (NIH) grants DK077097 (to Y.-H.T.); DK082659 (to C.R.K); and DK046200, DK081604 and RR025757 (to A.M.C.). And grants to the Joslin Diabetes Center's Diabetes and Endocrinology Research Center (P30 DK036836 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)). Work was also supported by funding from the Harvard Stem Cell Institute (to Y.-H.T.); the Harvard Catalyst/Harvard Clinical and Translational Science Center, RR025758 (to Y.-H.T. and A.M.C.). The content herein is solely the responsibility of the authors and does not necessarily represent the official views of the NIDDK or the NIH.
The authors declare no competing financial interests.
- Standard metabolic rate
The steady-state rate of energy utilized by a whole organism that is awake but resting, stress free, not actively digesting food, and is at thermoneutrality.
- Basal metabolic rate
(BMR). The energy expended by an individual when physically and mentally at rest 12–18 hours after a meal in a thermoneutral environment. It is similar to the standard metabolic rate, although it is now usually applied to human metabolism only.
The environmental temperature at which heat production is not stimulated, e.g., ∼28°C for adult humans. In general, humans usually make the microclimate thermoneutral through clothing choices.
- Adaptive thermogenesis
Heat production in response to environmental temperature or diet. It serves the purpose of protecting the organism from cold exposure or regulating energy balance after changes in diet. Brown fat and skeletal muscle are the two principal sites of adaptive thermogenesis.
Studies the flow of chemical bond energy within organisms. In a living cell, the principal reactions of fuel metabolism take place in the mitochondria, where food energy is released, oxygen is consumed, and water and carbon dioxide are produced.
Coupled in this article refers to processes in which the energy released by one reaction is directly used to drive another one; e.g., protons rushing into the mitochondrial matrix is coupled to ATP production.
Uncoupled in this article refers to processes in which the energy released is not used by the cell to drive another process; e.g., ion leak.
- Diet-induced thermogenesis
The heat produced in response to diet that allows excessive calorific intake. It primarily occurs in brown fat.
- Resting metabolic rate
The amount of energy expended at rest. It is also similar to the standard metabolic rate, except that the metabolic rate is measured while the organism is still digesting food.
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Tseng, YH., Cypess, A. & Kahn, C. Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov 9, 465–482 (2010). https://doi.org/10.1038/nrd3138
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