Brown Adipose Tissue: A New Target for Antiobesity Therapy

Anna Meiliana, Andi Wijaya


BACKGROUND: Human fat consist of white and brown adipose tissue (WAT and BAT). Though most fat is energy-storing WAT, the thermogenic capacity of even small amounts of BAT makes it an attractive therapeutic target for inducing weight loss through energy expenditure.

CONTENT: Over the past year, several independent research teams used a combination of positron-emission tomography and computed tomography (PET/CT) imaging, immunohistochemistry and gene and protein expression assays to prove conclusively that adult humans have functional BAT. BAT is important for thermogenesis and energy balance in small mammals and its induction in mice promotes energy expenditure, reduces adiposity and protects mice from diet-induced obesity. The thermogenic capacity of BAT is impressive. In humans, it has been estimated that as little as 50g of BAT could utilize up to 20% of basal caloric needs if maximally stimulated.

SUMMARY: The obesity pandemic requires new and novel treatments. The past few years have witnessed multiple studies conclusively showing that adult humans have functional BAT, a tissue that has a tremendous capacity for obesity-reducing thermogenesis. Novel therapies targeting BAT thermogenesis may be available in the near future as therapeutic options for obesity and diabetes. Thermogenic ingredients may be considered as functional agents that could help in preventing a positive energy balance and obesity.

KEYWORDS: brown adipose tissue, thermogenesis, energy expenditure, antiobesity therapy

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Bellisari A. Evolutionary origins of obesity. Obes Rev. 2008; 9: 165-80, CrossRef.

Celi FS. Brown adipose tissue: When it pays to be inefficient. N Engl J Med. 2009; 360: 1553-6, CrossRef.

Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell. 2007; 131: 242-56, CrossRef.

Cannon B, Nedergaard J. Brown adipose tissue: function and physiological signifi cance. Physiol Rev. 2004; 84: 277-359, CrossRef.

Silva JE, Larsen PR. Adrenergic activation of triiodothyronine production in brown adipose tissue. Nature. 1983; 305: 712-3, CrossRef.

Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006; 439: 484-9, CrossRef.

Crisan M, Casteilla L, Lehr L, Carmona M, Paoloni-Giacobino A, Yap S, et al. A reservoir of brown adipocyte progenitors in human skeletal muscle. Stem Cells. 2008; 26: 2425-33, CrossRef.

Heaton JM. The distribution of brown adipose tissue in the human. J Anat. 1972; 112: 35-9, PMID.

Astrup A. Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation. Acta Endocrinol Suppl. 1986; 278: 1-32, CrossRef.

Weyer C, Tataranni PA, Snitker S, Danforth E, Ravussin E. Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly-selective beta3-adrenoceptor agonist in humans. Diabetes. 1998; 47: 1555-61, CrossRef.

Larsen TM, Toubro S, van Baak MA, Gottesdiener KM, Larson P, Saris WH, et al. Effect of 28-d treatment with L-796568, a novel beta(3)-adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am J Clin Nutr 2002; 76: 780-8, PMID.

Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007; 293: E444-52, CrossRef.

Cunningham S, Leslie P, Hopwood D, Illingworth P, Jung RT, Nicholls DG, et al. The characterization and energetic potential of brown adipose tissue in man. Clin Sci. 1985; 69: 343-8, CrossRef.

Schoder H, Larson SM, Yeung HW. PET/CT in oncology: integration into clinical management of lymphoma, melanoma, and gastrointestinal malignancies. J Nucl Med. 2004; 45 (Suppl 1): 72S-81S, PMID.

Hany TF, Gharehpapagh E, Kamel EM, Buck A, Himms-Hagen J, von Schulthess GK. Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur J Nucl Med Mol Imaging. 2002; 29: 1393-8, CrossRef.

Cohade C, Osman M, Pannu HK, Wahl RL. Uptake in supraclavicular area fat (“USA fat”): description on 18FFDG PET/CT. J Nucl Med. 2003; 44: 170-6, PMID.

van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JMAFL, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009; 360: 1500-8, CrossRef.

Saito M, Okamatsu-Ogura Y, Matsushita M Watanabe K, Yoneshiro T, Nio-Kobayashi J, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans. Effects of cold exposure and adiposity. Diabetes. 2009; 58: 1526-31, CrossRef.

Enerbäck S. Human brown adipose tissue. Cell Metab. 2010; 11: 248-52, CrossRef.

Cannon B, Nedergaard J. Brown adipose tissue: function and physiological signifi cance. Physiol Rev. 2004; 84: 277-359, CrossRef.

Frontini A, Cinti S. Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab. 2010; 11: 253-6, CrossRef.

Bachman ES, Dhillon H, Zhang CY, et al. betaAR signaling required for diet-induced thermogenesis and obesity resistance. Science. 2002; 297: 843-5, CrossRef.

Kopecky J, Clarke G, Enerbäck S, Spiegelman B, Kozak LP. Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J Clin Invest. 1995; 96: 2914-23, CrossRef.

Kozak LP. Brown fat and the myth of diet-induced thermogenesis. Cell Metab. 2010; 11: 263-7, CrossRef.

Foster DO, Frydman ML. Nonshivering thermogenesis in the rat. II. Measurements of blood fl ow with microspheres point to brown adipose tissue as the dominant site of the calorigenesis induced by noradrenaline. Can J Physiol Pharmacol. 1978; 56: 110-22, CrossRef.

Farmer SR. Transcriptional control of adipocyte formation. Cell Metab. 2006; 4: 263-73, CrossRef.

Kajimura S, Seale P, Spiegelman BM. Transcriptional control of brown fat development. Cell Metab 2010; 11: 257-62, CrossRef.

Cederberg A, Grønning LM, Ahrén B, Taskén K, Carlsson P, Enerbäck S. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and dietinduced insulin resistance. Cell. 2001; 106: 563-73, CrossRef.

Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998; 92: 829-39, CrossRef.

Leonardsson G, Steel JH, Christian M, Pocock V, Milligan S, Bell J, et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc Natl Acad Sci USA. 2004; 101: 8437-42, CrossRef.

Picard F, Géhin M, Annicotte J, Rocchi S, Champy MF, O’Malley BW, et al. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell. 2002; 111: 931-41, CrossRef.

Hansen JB, Jørgensen C, Petersen RK, Hallenborg P, De Matteis R, Boye HA, et al. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc Natl Acad Sci USA. 2004; 101: 4112-7, CrossRef.

Scimè A, Grenier G, Huh MS, Gillespie MA, Bevilacqua L, Harper ME, et al. Rb and p107 regulate preadipocyte differentiation into white versus brown fat through repression of PGC-1alpha. Cell Metab. 2005; 2: 283-95, CrossRef.

Pan D, Fujimoto M, Lopes A, Wang YX. Twist-1 is a PPARdeltainducible, negative-feedback regulator of PGC-1alpha in brown fat metabolism. Cell. 2009; 137: 73-86, CrossRef.

Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J, et al. A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Blood. 2000; 96: 3209-14, PMID.

Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 2007; 6: 38-54, CrossRef.

Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008; 454: 961-7, CrossRef.

Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009; 460: 1154-8, CrossRef.

Karamitri A, Shore AM, Docherty K, Speakman JR, Lomax MA. Combinatorial transcription factor regulation of the cyclic AMP-response element on the Pgc-1alpha promoter in white 3T3-L1 and brown HIB-1B preadipocytes. J Biol Chem. 2009; 284: 20738-52, CrossRef.

Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 2008; 454: 1000-4, CrossRef.

Shen JJ, Huang L, Li L, Jorgez C, Matzuk MM, Brown CW. Deficiency of growth differentiation factor 3 protects against diet-induced obesity by selectively acting on white adipose. Mol Endocrinol. 2009; 23: 113-23, CrossRef.

Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, et al. Inhibition of adipogenesis by Wnt signaling. Science. 2000; 28: 950-3, CrossRef.

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. 2000; 275: 12119-22, CrossRef.

Nedergaard J, Cannon B. The changed metabolic world with human brown adipose tissue: therapeutic visions. Cell Metab. 2010; 11: 268-72, CrossRef.

Melnikova I, Wages D. Anti-obesity therapies. Nat Rev Drug Discov. 2006; 5: 369-70, CrossRef.

Shekelle PG, Hardy ML, Morton SC, Maglione M, Mojica WA, Suttorp MJ, et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA. 2003; 289: 1537-45, CrossRef.

Arch JR. The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspective from beta3-adrenoreceptor agonists. Naunyn Schmiedebergs Arch Pharmacol. 2008; 378: 225-40, CrossRef.

Tiwari A, Maiti P. TGR5: an emerging bile acid G-protein-coupled receptor target for the potential treatment of metabolic disorders. Drug Discov Today. 2009; 14: 523-30, CrossRef.

Thomas C, Gioielio A, Noriega L, Strehle A, Oury J, Rizzo G, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009; 10: 167-77, CrossRef.

Kendall DM, Rubin CJ, Mohideen P, Ledeine JM, Belder R, Gross J, et al. Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a double-blind, randomized, pioglitazone-comparative study. Diab Care. 2006; 29: 1016-23, CrossRef.

Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M. Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomized, dose-ranging study. Lancet. 2009; 374: 126-36, CrossRef.

Yamamoto H, Schoonjans K, Auwerx J. Sirtuin functions in health and disease. Mol Endocrinol. 2007; 21: 1745-55, CrossRef.

Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, et al. Peroxisome proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell. 2003; 113: 159-70, CrossRef.

Harper ME, Green K, Brand MD. The efficiency of cellular energy transduction and its implications for obesity. Annu Rev Nutr. 2008; 28: 13-33, CrossRef.

Clapham JC, Arch JR. Thermogenic and metabolic antiobesity drugs: rationale and opportunities. Diabetes Obes Metab. 2007; 9: 259-75, CrossRef.

Van Baak MA, Hui GB, Toubro S, Astrup A, Gottesdiener KM, DeSmet M, et al. Acute effect of L-796568, a novel beta 3-adrenergic receptor agonist, on energy expenditure in obese men. Clin Pharmacol Ther. 2002; 71: 272-9, CrossRef.

Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARaplha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007; 5: 426-37, CrossRef.

Cypess AM, Kahn CR. Brown fat as a therapy for obesity and diabetes. Curr Opin Endocrinol. 2010; 17: 143-9, CrossRef.

Vernochet C, Peres SB, Davis KE, McDonald ME, Qiang L, Wang H, et al. C/EBPalpha and the corepresors CtBP1 and CtBP2 regulate repression of select visceral white adipose genes during induction of the brown phenotype in white adipocytes by peroxisome proliferator-activated receptor gamma agonists. Mol Cell Biol. 2009; 29: 4714-28, CrossRef.

Rothwell NJ, Stock MJ. Luxuskonsumption, diet-induced thermogenesis and brown fat: the case in favour. Clin Sci. 1983; 64: 19-23, CrossRef.

Almind K, Manieri M, Sivitz WI, Cinti S, Kahn CR. Ectopic brown adipose tissue in muscle provides a mechanisms for differences in risk of metabolic syndrome in mice. Proc Natl Acad Sci USA. 2007; 104: 2366-71, CrossRef.

Xue B, Rim JS, Hogan CJ, Coulter AA, Koza RA, Kozak LP, et al. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J Lipid Res. 2007; 48: 41-51, CrossRef.

Hursel R, Westerterp-Plantenga MS. Thermogenic ingredients and body weight regulation. Int J Obes. 2010; 34: 659-69, CrossRef.

Dulloo AG, Duret C, Rohrer D, Girardier L, Mensi N, Fathi M, et al. Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans. Am J Clin Nutr 1999; 70: 1040-5, PMID.

Westerterp-Plantenga MS, Lejeune MP, Kovacs EM. Body weight loss and weight maintenance in relation to habitual caffeine intake and green tea supplementation. Obes Res. 2005; 13: 1195-204, CrossRef.

Shixian Q, VanCrey B, Shi J, Kakuda Y, Jiang Y. Green tea extract thermogenesis-induced weight loss by epigallocatechin gallate inhibition of catechol-O-methyltransferase. J Med Food. 2006; 9: 451-8, CrossRef.

Cornelis MC, El-Sohemy A, Campos H. Genetic polymorphism of the adenosine A2A receptor is associated with habitual caffeine consumption. Am J Clin Nutr. 2007; 86: 240-4, PMID.

Acheson KJ, Gremaud G, Meirim I, Montigon F, Krebs Y, Fay LB, et al. Metabolic effects of caffeine in humans: lipid oxidation or futile cycling? Am J Clin Nutr. 2004; 79: 40-6, PMID.

Belza A, Frandsen E, Kondrup J. Body fat loss achieved by stimulation of thermogenesis by a combination of bioactive food ingredients: a placebo-controlled, doubleblind 8-week intervention in obese subjects. Int J Obes. 2007; 31: 121-30, CrossRef.

Masuda Y, Haramizu S, Oki K, Ohnuki K, Watanabe T, Yazawa S, et al. Upregulation of uncoupling proteins by oral administration of capsiate, a nonpungent capsaicin analog. J Appl Physiol. 2003; 95: 2408-15, CrossRef.


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