Jingxin Liu, Yitao Wang, Ligen Lin. Small molecules for fat combustion: targeting obesity[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 220-236

Small molecules for fat combustion: targeting obesity
Jingxin Liu, Yitao Wang, Ligen Lin
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa 999078, Macau, China
Obesity is increasing in an alarming rate worldwide, which causes higher risks of some diseases, such as type 2 diabetes, cardiovascular diseases, and cancer. Current therapeutic approaches, either pancreatic lipase inhibitors or appetite suppressors, are generally of limited effectiveness. Brown adipose tissue (BAT) and beige cells dissipate fatty acids as heat to maintain body temperature, termed non-shivering thermogenesis; the activity and mass of BAT and beige cells are negatively correlated with overweight and obesity. The existence of BAT and beige cells in human adults provides an effective weight reduction therapy, a process likely to be amenable to pharmacological intervention. Herein, we combed through the physiology of thermogenesis and the role of BAT and beige cells in combating with obesity. We summarized the thermogenic regulators identified in the past decades, targeting G proteincoupled receptors, transient receptor potential channels, nuclear receptors and miscellaneous pathways. Advances in clinical trials were also presented. The main purpose of this review is to provide a comprehensive and up-to-date knowledge from the biological importance of thermogenesis in energy homeostasis to the representative thermogenic regulators for treating obesity. Thermogenic regulators might have a large potential for further investigations to be developed as lead compounds in fighting obesity.
Key words:    Thermogenesis    Brown adipose tissue    Beige cells    Obesity    Uncoupling protein 1   
Received: 2018-04-27     Revised: 2018-08-01
DOI: 10.1016/j.apsb.2018.09.007
Funds: Financial support by Science and Technology Development Fund,Macao SAR,China (FDCT 102/2017/A) and the Research Fund of University of Macau,China (MYRG2017-00109-ICMS) are gratefully acknowledged.
Corresponding author: Ligen Lin
Author description:
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Jingxin Liu
Yitao Wang
Ligen Lin

1. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013:a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014;384:766-81.
2. Gallagher EJ, LeRoith D. Obesity and diabetes:the increased risk of cancer and cancer-related mortality. Physiol Rev 2015;95:727-48.
3. Lovren F, Teoh H, Verma S. Obesity and atherosclerosis:mechanistic insights. Can J Cardiol 2015;31:177-83.
4. Deng T, Lyon CJ, Bergin S, Caligiuri MA, Hsueh WA. Obesity, inflammation, and cancer. Annu Rev Pathol 2016;11:421-49.
5. Himbert C, Delphan M, Scherer D, Bowers LW, Hursting S, Ulrich CM. Signals from the adipose microenvironment and the obesity-cancer link-a systematic review. Cancer Prev Res 2017;10:494-506.
6. Park J, Morley TS, Kim M, Clegg DJ, Scherer PE. Obesity and cancer-mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol 2014;10:455-65.
7. Daneschvar HL, Aronson MD, Smetana GW. FDA-approved antiobesity drugs in the United States. Am J Med 2016;129:879. e1-6.
8. Cannon B, Nedergaard J. Brown adipose tissue:function and physiological significance. Physiol Rev 2004;84:277-359.
9. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012;150:366-76.
10. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009;360:1509-17.
11. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009;360:1500-8.
12. Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elia E, Kessler SH, Kahn PA, et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab 2015;21:33-8.
13. Atgie C, D'Allaire F, Bukowiecki LJ. Role of b1-and b3-adrenoceptors in the regulation of lipolysis and thermogenesis in rat brown adipocytes. Am J Physiol 1997;273:C1136-42.
14. Xiao C, Goldgof M, Gavrilova O, Reitman ML. Anti-obesity and metabolic efficacy of the β3-adrenergic agonist, CL316243, in mice at thermoneutrality compared to 22 degrees C. Obesity 2015;23:1450-9.
15. Weyer C, Tataranni PA, Snitker S, Danforth Jr. E, Ravussin E. Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective β3-adrenoceptor agonist in humans. Diabetes 1998;47:1555-61.
16. Larsen TM, Toubro S, van Baak MA, Gottesdiener KM, Larson P, Saris WH, 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 2002;76:780-8.
17. van Baak MA, Hul GB, Toubro S, Astrup A, Gottesdiener KM, DeSmet M, et al. Acute effect of L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure in obese men. Clin Pharmacol Ther 2002;71:272-9.
18. Oliver P, Pico C, Martinez N, Bonet ML, Palou A. In vivo effects of CGP-12177 on the expression of leptin and uncoupling protein genes in mouse brown and white adipose tissues. Int J Obes Relat Metab Disord 2000;24:423-8.
19. Pico C, Bonet ML, Palou A. Stimulation of uncoupling protein synthesis in white adipose tissue of mice treated with the β3-adrenergic agonist CGP-12177. Cell Mol Life Sci 1998;54:191-5.
20. Zhao J, Golozoubova V, Cannon B, Nedergaard J. Arotinolol is a weak partial agonist on β3-adrenergic receptors in brown adipocytes. Can J Physiol Pharmacol 2001;79:585-93.
21. Buemann B, Toubro S, Astrup A. Effects of the two β3-agonists, ZD7114 and ZD2079 on 24 h energy expenditure and respiratory quotient in obese subjects. Int J Obes Relat Metab Disord 2000;24:1553-60.
22. Redman LM, de Jonge L, Fang X, Gamlin B, Recker D, Greenway FL, et al. Lack of an effect of a novel β3-adrenoceptor agonist, TAK-677, on energy metabolism in obese individuals:a double-blind, placebo-controlled randomized study. J Clin Endocrinol Metab 2007;92:527-31.
23. Schimmel RJ, McCarthy L. Role of adenosine as an endogenous regulator of respiration in hamster brown adipocytes. Am J Physiol 1984;246:C301-7.
24. Fain JN, Pointer RH, Ward WF. Effects of adenosine nucleosides on adenylate cyclase, phosphodiesterase, cyclic adenosine monophosphate accumulation, and lipolysis in fat cells. J Biol Chem 1972;247:6866-72.
25. Gnad T, Scheibler S, von Kugelgen I, Scheele C, Kilic A, Glode A, et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 2014;516:395-9.
26. Ding L, Yang L, Wang Z, Huang W. Bile acid nuclear receptor FXR and digestive system diseases. Acta Pharm Sin B 2015;5:135-44.
27. Zhu Y, Liu H, Zhang M, Guo GL. Fatty liver diseases, bile acids, and FXR. Acta Pharm Sin B 2016;6:409-12.
28. 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.
29. Liaset B, Hao Q, Jorgensen H, Hallenborg P, Du ZY, Ma T, et al. Nutritional regulation of bile acid metabolism is associated with improved pathological characteristics of the metabolic syndrome. J Biol Chem 2011;286:28382-95.
30. Broeders EP, Nascimento EB, Havekes B, Brans B, Roumans KH, Tailleux A, et al. The bile acid chenodeoxycholic acid increases human brown adipose tissue activity. Cell Metab 2015;22:418-26.
31. Venkatachalam K, Montell C. TRP channels. Annu Rev Biochem 2007;76:387-417.
32. Yoneshiro T, Saito M. Transient receptor potential activated brown fat thermogenesis as a target of food ingredients for obesity management. Curr Opin Clin Nutr Metab Care 2013;16:625-31.
33. Snitker S, Fujishima Y, Shen H, Ott S, Pi-Sunyer X, Furuhata Y, et al. Effects of novel capsinoid treatment on fatness and energy metabolism in humans:possible pharmacogenetic implications. Am J Clin Nutr 2009;89:45-50.
34. Inoue N, Matsunaga Y, Satoh H, Takahashi M. Enhanced energy expenditure and fat oxidation in humans with high BMI scores by the ingestion of novel and non-pungent capsaicin analogues (capsinoids). Biosci Biotechnol Biochem 2007;71:380-9.
35. Nirengi S, Homma T, Inoue N, Sato H, Yoneshiro T, Matsushita M, et al. Assessment of human brown adipose tissue density during daily ingestion of thermogenic capsinoids using nearinfrared time-resolved spectroscopy. J Biomed Opt 2016;21:091305.
36. Yoneshiro T, Aita S, Kawai Y, Iwanaga T, Saito M. Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans. Am J Clin Nutr 2012;95:845-50.
37. Whiting S, Derbyshire E, Tiwari BK. Capsaicinoids and capsinoids. a potential role for weight management? A systematic review of the evidence. Appetite 2012;59:341-8.
38. Lejeune MP, Kovacs EM, Westerterp-Plantenga MS. Effect of capsaicin on substrate oxidation and weight maintenance after modest body-weight loss in human subjects. Br J Nutr 2003;90:651-9.
39. Chen J, Li L, Li Y, Liang X, Sun Q, Yu H, et al. Activation of TRPV1 channel by dietary capsaicin improves visceral fat remodeling through connexin43-mediated Ca2+ influx. Cardiovasc Diabetol 2015;14:22.
40. Iwasaki Y, Tamura Y, Inayoshi K, Narukawa M, Kobata K, Chiba H, et al. TRPV1 agonist monoacylglycerol increases UCP1 content in brown adipose tissue and suppresses accumulation of visceral fat in mice fed a high-fat and high-sucrose diet. Biosci Biotechnol Biochem 2011;75:904-9.
41. Kim M, Furuzono T, Yamakuni K, Li Y, Kim YI, Takahashi H, et al. 10-Oxo-12(Z)-octadecenoic acid, a linoleic acid metabolite produced by gut lactic acid bacteria, enhances energy metabolism by activation of TRPV1. FASEB J 2017;31:5036-48.
42. Hochkogler CM, Lieder B, Rust P, Berry D, Meier SM, Pignitter M, et al. A 12-week intervention with nonivamide, a TRPV1 agonist, prevents a dietary-induced body fat gain and increases peripheral serotonin in moderately overweight subjects. Mol Nutr Food Res 2017;61:1600731.
43. Sun W, Uchida K, Suzuki Y, Zhou Y, Kim M, Takayama Y, et al. Lack of TRPV2 impairs thermogenesis in mouse brown adipose tissue. EMBO Rep 2016;17:383-99.
44. Sun WP, Uchida K, Takahashi N, Iwata Y, Wakabayashi S, Goto T, et al. Activation of TRPV2 negatively regulates the differentiation of mouse brown adipocytes. Pflugers Arch 2016;468:1527-40.
45. Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, et al. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 2000;103:525-35.
46. Ye L, Kleiner S, Wu J, Sah R, Gupta RK, Banks AS, et al. TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell 2012;151:96-110.
47. Vizin RC, Scarpellini Cda S, Ishikawa DT, Correa GM, de Souza CO, Gargaglioni LH, et al. TRPV4 activates autonomic and behavioural warmth-defence responses in Wistar rats. Acta Physiol 2015;214:275-89.
48. Voets T, Owsianik G, Janssens A, Talavera K, Nilius B. TRPM8 voltage sensor mutants reveal a mechanism for integrating thermal and chemical stimuli. Nat Chem Biol 2007;3:174-82.
49. Colburn RW, Lubin ML, Stone Jr. DJ, Wang Y, Lawrence D, D'Andrea MR, et al. Attenuated cold sensitivity in TRPM8 null mice. Neuron 2007;54:379-86.
50. Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 2007;448:204-8.
51. Masamoto Y, Kawabata F, Fushiki T. Intragastric administration of TRPV1, TRPV3, TRPM8, and TRPA1 agonists modulates autonomic thermoregulation in different manners in mice. Biosci Biotechnol Biochem 2009;73:1021-7.
52. Ma S, Yu H, Zhao Z, Luo Z, Chen J, Ni Y, et al. Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity. J Mol Cell Biol 2012;4:88-96.
53. Evans RM, Mangelsdorf DJ. Nuclear receptors, RXR, and the big bang. Cell 2014;157:255-66.
54. van Bilsen M, van der Vusse GJ, Gilde AJ, Lindhout M, van der Lee KA. Peroxisome proliferator-activated receptors:lipid binding proteins controling gene expression. Mol Cell Biochem 2002;239:131-8.
55. Roberts LD, Murray AJ, Menassa D, Ashmore T, Nicholls AW, Griffin JL. The contrasting roles of PPARδ and PPARγ in regulating the metabolic switch between oxidation and storage of fats in white adipose tissue. Genome Biol 2011;12:R75.
56. Castelein H, Gulick T, Declercq PE, Mannaerts GP, Moore DD, Baes MI. The peroxisome proliferator activated receptor regulates malic enzyme gene expression. J Biol Chem 1994;269:26754-8.
57. Wilson-Fritch L, Burkart A, Bell G, Mendelson K, Leszyk J, Nicoloro S, et al. Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone. Mol Cell Biol 2003;23:1085-94.
58. Elabd C, Chiellini C, Carmona M, Galitzky J, Cochet O, Petersen R, et al. Human multipotent adipose-derived stem cells differentiate into functional brown adipocytes. Stem Cells 2009;27:2753-60.
59. Petrovic N, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Thermogenically competent nonadrenergic recruitment in brown preadipocytes by a PPARγ agonist. Am J Physiol Endocrinol Metab 2008;295:E287-96.
60. Festuccia WT, Blanchard PG, Richard D, Deshaies Y. Basal adrenergic tone is required for maximal stimulation of rat brown adipose tissue UCP1 expression by chronic PPAR-γ activation. Am J Physiol Regul Integr Comp Physiol 2010;299:R159-67.
61. Festuccia WT, Blanchard PG, Oliveira TB, Magdalon J, Paschoal VA, Richard D, et al. PPARγ activation attenuates cold-induced upregulation of thyroid status and brown adipose tissue PGC-1a and D2. Am J Physiol Regul Integr Comp Physiol 2012;303:R1277-85.
62. Bogacka I, Xie H, Bray GA, Smith SR. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 2005;54:1392-9.
63. Chen HY, Liu Q, Salter AM, Lomax MA. Synergism between cAMP and PPARγ signalling in the initiation of UCP1 gene expression in HIB1B brown adipocytes. PPAR Res 2013;2013:476049.
64. Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ, et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell 2012;148:556-67.
65. Zhang Z, Zhang H, Li B, Meng X, Wang J, Zhang Y, et al. Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun 2014;5:5493.
66. Rigano D, Sirignano C, Taglialatela-Scafati O. The potential of natural products for targeting PPARa. Acta Pharm Sin B 2017;7:427-38.
67. Barbera MJ, Schluter A, Pedraza N, Iglesias R, Villarroya F, Giralt M. Peroxisome proliferator-activated receptor α activates transcription of the brown fat uncoupling protein-1 gene. A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell. J Biol Chem 2001;276:1486-93.
68. Lee JY, Hashizaki H, Goto T, Sakamoto T, Takahashi N, Kawada T. Activation of peroxisome proliferator-activated receptor-alpha enhances fatty acid oxidation in human adipocytes. Biochem Biophys Res Commun 2011;407:818-22.
69. Ribet C, Montastier E, Valle C, Bezaire V, Mazzucotelli A, Mairal A, et al. Peroxisome proliferator-activated receptor-alpha control of lipid and glucose metabolism in human white adipocytes. Endocrinology 2010;151:123-33.
70. Hondares E, Rosell M, Diaz-Delfin J, Olmos Y, Monsalve M, Iglesias R, et al. Peroxisome proliferator-activated receptor alpha (PPARalpha) induces PPARγ coactivator 1alpha (PGC-1alpha) gene expression and contributes to thermogenic activation of brown fat:involvement of PRDM16. J Biol Chem 2011;286:43112-22.
71. Suarez J, Rivera P, Arrabal S, Crespillo A, Serrano A, Baixeras E, et al. Oleoylethanolamide enhances β-adrenergic-mediated thermogenesis and white-to-brown adipocyte phenotype in epididymal white adipose tissue in rat. Dis Model Mec 2014;7:129-41.
72. Schug TT, Berry DC, Shaw NS, Travis SN, Noy N. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 2007;129:723-33.
73. Berry DC, Noy N. All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor β/δ and retinoic acid receptor. Mol Cell Biol 2009;29:3286-96.
74. Juvet LK, Andresen SM, Schuster GU, Dalen KT, Tobin KA, Hollung K, et al. On the role of liver X receptors in lipid accumulation in adipocytes. Mol Endocrinol 2003;17:172-82.
75. Seo JB, Moon HM, Kim WS, Lee YS, Jeong HW, Yoo EJ, et al. Activated liver X receptors stimulate adipocyte differentiation through induction of peroxisome proliferator-activated receptor γ expression. Mol Cell Biol 2004;24:3430-44.
76. Hummasti S, Laffitte BA, Watson MA, Galardi C, Chao LC, Ramamurthy L, et al. Liver X receptors are regulators of adipocyte gene expression but not differentiation:identification of apoD as a direct target. J Lipid Res 2004;45:616-25.
77. Zheng F, Zhang S, Lu W, Wu F, Yin X, Yu D, et al. Regulation of insulin resistance and adiponectin signaling in adipose tissue by liver X receptor activation highlights a cross-talk with PPARγ. PLoS One 2014;9:e101269.
78. Gu M, Zhang Y, Liu C, Wang D, Feng L, Fan S, et al. Morin, a novel liver X receptor alpha/β dual antagonist, has potent therapeutic efficacy for nonalcoholic fatty liver diseases. Br J Pharmacol 2017;174:3032-44.
79. Shu L, Hoo RL, Wu X, Pan Y, Lee IP, Cheong LY, et al. A-FABP mediates adaptive thermogenesis by promoting intracellular activation of thyroid hormones in brown adipocytes. Nat Commun 2017;8:14147.
80. Korach-Andre M, Archer A, Barros RP, Parini P, Gustafsson JA. Both liver-X receptor (LXR) isoforms control energy expenditure by regulating brown adipose tissue activity. Proc Natl Acad Sci U S A 2011;108:403-8.
81. Stenson BM, Ryden M, Steffensen KR, Wahlen K, Pettersson AT, Jocken JW, et al. Activation of liver X receptor regulates substrate oxidation in white adipocytes. Endocrinology 2009;150:4104-13.
82. Dib L, Bugge A, Collins S. LXRalpha fuels fatty acid-stimulated oxygen consumption in white adipocytes. J Lipid Res 2014;55:247-57.
83. Sheng X, Zhu X, Zhang Y, Cui G, Peng L, Lu X, et al. Rhein protects against obesity and related metabolic disorders through liver X receptor-mediated uncoupling protein 1 upregulation in brown adipose tissue. Int J Biol Sci 2012;8:1375-84.
84. Sun H, Luo G, Chen D, Xiang Z. A comprehensive and system review for the pharmacological mechanism of action of rhein, an active anthraquinone ingredient. Front Pharmacol 2016;7:247.
85. Rabelo R, Reyes C, Schifman A, Silva JE. A complex retinoic acid response element in the uncoupling protein gene defines a novel role for retinoids in thermogenesis. Endocrinology 1996;137:3488-96.
86. Alvarez R, de Andres J, Yubero P, Vinas O, Mampel T, Iglesias R, et al. A novel regulatory pathway of brown fat thermogenesis. retinoic acid is a transcriptional activator of the mitochondrial uncoupling protein gene. J Biol Chem 1995;270:5666-73.
87. Puigserver P, Vazquez F, Bonet ML, Pico C, Palou A. In vitro and in vivo induction of brown adipocyte uncoupling protein (thermogenin) by retinoic acid. Biochem J 1996;317:827-33.
88. Kumar MV, Sunvold GD, Scarpace PJ. Dietary vitamin A supplementation in rats:suppression of leptin and induction of UCP1 mRNA. J Lipid Res 1999;40:824-9.
89. Bonet ML, Oliver J, Pico C, Felipe F, Ribot J, Cinti S, et al. Opposite effects of feeding a vitamin A-deficient diet and retinoic acid treatment on brown adipose tissue uncoupling protein 1 (UCP1), UCP2 and leptin expression. J Endocrinol 2000;166:511-7.
90. Alvarez R, Checa M, Brun S, Vinas O, Mampel T, Iglesias R, et al. Both retinoic-acid-receptor-and retinoid-X-receptor-dependent signalling pathways mediate the induction of the brown-adipose-tissueuncoupling-protein-1 gene by retinoids. Biochem J 2000;345:91-7.
91. Teruel T, Hernandez R, Benito M, Lorenzo M. Rosiglitazone and retinoic acid induce uncoupling protein-1 (UCP-1) in a p38 mitogenactivated protein kinase-dependent manner in fetal primary brown adipocytes. J Biol Chem 2003;278:263-9.
92. Berry DC, DeSantis D, Soltanian H, Croniger CM, Noy N. Retinoic acid upregulates preadipocyte genes to block adipogenesis and suppress diet-induced obesity. Diabetes 2012;61:1112-21.
93. McIlroy GD, Tammireddy SR, Maskrey BH, Grant L, Doherty MK, Watson DG, et al. Fenretinide mediated retinoic acid receptor signalling and inhibition of ceramide biosynthesis regulates adipogenesis, lipid accumulation, mitochondrial function and nutrient stress signalling in adipocytes and adipose tissue. Biochem Pharmacol 2016;100:86-97.
94. Murholm M, Isidor MS, Basse AL, Winther S, Sorensen C, Skovgaard-Petersen J, et al. Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes. BMC Cell Biol 2013;14:41.
95. Kamei Y, Kawada T, Kazuki R, Ono T, Kato S, Sugimoto E. Vitamin D receptor gene expression is up-regulated by 1,25-dihydroxyvitamin D3 in 3T3-L1 preadipocytes. Biochem Biophys Res Commun 1993;193:948-55.
96. Fu M, Sun T, Bookout AL, Downes M, Yu RT, Evans RM, et al. A nuclear receptor atlas:3T3-l1 adipogenesis. Mol Endocrinol 2005;19:2437-50.
97. Ricciardi CJ, Bae J, Esposito D, Komarnytsky S, Hu P, Chen J, et al. 1,25-Dihydroxyvitamin D3/vitamin D receptor suppresses brown adipocyte differentiation and mitochondrial respiration. Eur J Nutr 2015;54:1001-12.
98. Narvaez CJ, Matthews D, Broun E, Chan M, Welsh J. Lean phenotype and resistance to diet-induced obesity in vitamin D receptor knockout mice correlates with induction of uncoupling protein-1 in white adipose tissue. Endocrinology 2009;150:651-61.
99. Wong KE, Szeto FL, Zhang W, Ye H, Kong J, Zhang Z, et al. Involvement of the vitamin D receptor in energy metabolism:regulation of uncoupling proteins. Am J Physiol Endocrinol Metab 2009;296:E820-8.
100. Wong KE, Kong J, Zhang W, Szeto FL, Ye H, Deb DK, et al. Targeted expression of human vitamin D receptor in adipocytes decreases energy expenditure and induces obesity in mice. J Biol Chem 2011;286:33804-10.
101. Bhat M, Noolu B, Qadri SS, Ismail A. Vitamin D deficiency decreases adiposity in rats and causes altered expression of uncoupling proteins and steroid receptor coactivator3. J Steroid Biochem Mol Biol 2014;144:304-12.
102. Malloy PJ, Feldman BJ. Cell-autonomous regulation of brown fat identity gene UCP1 by unliganded vitamin D receptor. Mol Endocrinol 2013;27:1632-42.
103. Brewer CT, Chen T. PXR variants:the impact on drug metabolism and therapeutic responses. Acta Pharm Sin B 2016;6:441-9.
104. He J, Gao J, Xu M, Ren S, Stefanovic-Racic M, O'Doherty RM, et al. PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice. Diabetes 2013;62:1876-87.
105. Ma Y, Liu D. Activation of pregnane X receptor by pregnenolone 16 alpha-carbonitrile prevents high-fat diet-induced obesity in AKR/J mice. PLoS One 2012;7:e38734.
106. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology 1998;139:4252-63.
107. Rodriguez-Cuenca S, Monjo M, Gianotti M, Proenza AM, Roca P. Expression of mitochondrial biogenesis-signaling factors in brown adipocytes is influenced specifically by 17β-estradiol, testosterone, and progesterone. Am J Physiol Endocrinol Metab 2007;292:E340-6.
108. Moreno AJ, Moreira PI, Custodio JB, Santos MS. Mechanism of inhibition of mitochondrial ATP synthase by 17b-estradiol. J Bioenerg Biomembr 2013;45:261-70.
109. Shughrue PJ, Lane MV, Merchenthaler I. Comparative distribution of estrogen receptor-alpha and -b mRNA in the rat central nervous system. J Comp Neurol 1997;388:507-25.
110. Martinez de Morentin PB, Gonzalez-Garcia I, Martins L, Lage R, Fernandez-Mallo D, Martinez-Sanchez N, et al. Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab 2014;20:41-53.
111. Grefhorst A, van den Beukel JC, van Houten EL, Steenbergen J, Visser JA, Themmen AP. Estrogens increase expression of bone morphogenetic protein 8b in brown adipose tissue of mice. Biol Sex Differ 2015;6:7.
112. Miao YF, Su W, Dai YB, Wu WF, Huang B, Barros RP, et al. An ERβ agonist induces browning of subcutaneous abdominal fat pad in obese female mice. Sci Rep 2016;6:38579.
113. Clarke SD, Clarke IJ, Rao A, Evans RG, Henry BA. Differential effects of acute and chronic estrogen treatment on thermogenic and metabolic pathways in ovariectomized sheep. Endocrinology 2013;154:184-92.
114. Ayala JE, Bracy DP, Julien BM, Rottman JN, Fueger PT, Wasserman DH. Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice. Diabetes 2007;56:1025-33.
115. Mitschke MM, Hoffmann LS, Gnad T, Scholz D, Kruithoff K, Mayer P, et al. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J 2013;27:1621-30.
116. Cassolla P, Uchoa ET, Mansur Machado FS, Guimaraes JB, Rissato Garofalo MA, de Almeida Brito N, et al. The central administration of C75, a fatty acid synthase inhibitor, activates sympathetic outflow and thermogenesis in interscapular brown adipose tissue. Pflugers Arch 2013;465:1687-99.
117. Shen W, Chuang CC, Martinez K, Reid T, Brown JM, Xi L, et al. Conjugated linoleic acid reduces adiposity and increases markers of browning and inflammation in white adipose tissue of mice. J Lipid Res 2013;54:909-22.
118. Shen W, Baldwin J, Collins B, Hixson L, Lee KT, Herberg T, et al. Low level of trans-10, cis-12 conjugated linoleic acid decreases adiposity and increases browning independent of inflammatory signaling in overweight Sv129 mice. J Nutr Biochem 2015;26:616-25.
119. Lynes MD, Leiria LO, Lundh M, Bartelt A, Shamsi F, Huang TL, et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat Med 2017;23:631-7.
120. Batubara I, Suparto IH, Sa'diah S, Matsuoka R, Mitsunaga T. Effects of inhaled citronella oil and related compounds on rat body weight and brown adipose tissue sympathetic nerve. Nutrients 2015;7:1859-70.
121. Batubara I, Suparto IH, Sadiah S, Matsuoka R, Mitsunaga T. Effect of Zingiber zerumbet essential oils and zerumbone inhalation on body weight of Sprague Dawley rat. Pak J Biol Sci 2013;16:1028-33.
122. Sugimoto S, Nakajima H, Kodo K, Mori J, Matsuo K, Kosaka K, et al. Miglitol increases energy expenditure by upregulating uncoupling protein 1 of brown adipose tissue and reduces obesity in dietary-induced obese mice. Nutr Metab 2014;11:14.
123. Haratake A, Watase D, Setoguchi S, Terada K, Matsunaga K, Takata J. Relationship between the acyl chain length of paradol analogues and their antiobesity activity following oral ingestion. J Agric Food Chem 2014;62:6166-74.
124. Galmozzi A, Sonne SB, Altshuler-Keylin S, Hasegawa Y, Shinoda K, Luijten IH, et al. ThermoMouse:an in vivo model to identify modulators of UCP1 expression in brown adipose tissue. Cell Rep 2014;9:1584-93.
125. Andrade JM, Frade AC, Guimaraes JB, Freitas KM, Lopes MT, Guimaraes AL, et al. Resveratrol increases brown adipose tissue thermogenesis markers by increasing SIRT1 and energy expenditure and decreasing fat accumulation in adipose tissue of mice fed a standard diet. Eur J Nutr 2014;53:1503-10.
126. Alberdi G, Rodriguez VM, Miranda J, Macarulla MT, Churruca I, Portillo MP. Thermogenesis is involved in the body-fat lowering effects of resveratrol in rats. Food Chem 2013;141:1530-5.
127. Kopecky J, Clarke G, Enerback S, Spiegelman B, Kozak LP. Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J Clin Investig 1995;96:2914-23.
128. Fu YY, Zhang M, Turner N, Zhang LN, Dong TC, Gu M, et al. A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake. Diabetologia 2013;56:2297-307.
129. Affourtit C, Crichton PG, Parker N, Brand MD. Novel uncoupling proteins. Novartis Found Symp 2007;287:70-91.
130. Echtay KS. Mitochondrial uncoupling proteins-what is their physiological role?. Free Radic Biol Med 2007;43:1351-71.
131. Diano S, Horvath TL. Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends Mol Med 2012;18:52-8.
132. Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K, Cohen P, et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 2015;163:643-55.
133. Ikeda K, Kang Q, Yoneshiro T, Camporez JP, Maki H, Homma M, et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat Med 2017;23:1454-65.
134. Ukropec J, Anunciado RP, Ravussin Y, Hulver MW, Kozak LP. UCP1-independent thermogenesis in white adipose tissue of coldacclimated Ucp1-/-mice. J Biol Chem 2006;281:31894-908.
135. Granneman JG, Burnazi M, Zhu Z, Schwamb LA. White adipose tissue contributes to UCP1-independent thermogenesis. Am J Physiol Endocrinol Metab 2003;285:E1230-6.
136. Sidossis L, Kajimura S. Brown and beige fat in humans:thermogenic adipocytes that control energy and glucose homeostasis. J Clin Investig 2015;125:478-86.
137. 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.
138. Abdullahi A, Jeschke MG. White adipose tissue browning:a doubleedged sword. Trends Endocrinol Metab 2016;27:542-52.
139. Lu S, Jang H, Gu S, Zhang J, Nussinov R. Drugging Ras GTPase:a comprehensive mechanistic and signaling structural view. Chem Soc Rev 2016;45:4929-52.
140. Shen Q, Cheng F, Song H, Lu W, Zhao J, An X, et al. Proteome-scale investigation of protein allosteric regulation perturbed by somatic mutations in 7000 cancer genomes. Am J Hum Genet 2017;100:5-20.
141. Tsou RC, Zimmer DJ, De Jonghe BC, Bence KK. Deficiency of PTP1B in leptin receptor-expressing neurons leads to decreased body weight and adiposity in mice. Endocrinology 2012;153:4227-37.
142. Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, et al. PTP1B regulates leptin signal transduction in vivo. Dev Cell 2002;2:489-95.
143. Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med 2006;12:917-24.
144. Li S, Zhang J, Lu S, Huang W, Geng L, Shen Q, et al. The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B. PLoS One 2014;9:e97668.
145. Huang W, Wang G, Shen Q, Liu X, Lu S, Geng L, et al. ASBench:benchmarking sets for allosteric discovery. Bioinformatics 2015;31:2598-600.
146. Yang T, Xiao T, Sun Q, Wang K. The current agonists and positive allosteric modulators of alpha7 nAChR for CNS indications in clinical trials. Acta Pharm Sin B 2017;7:611-22.
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