Targeting adipose tissue in the treatment of obesity-associated diabetes (original) (raw)

• Van Gaal, L. F., Mertens, I. L. & De Block, C. E. Mechanisms linking obesity with cardiovascular disease. Nature 444, 875–880 (2006).
  CAS PubMed Google Scholar
• Kusminski, C. M., Shetty, S., Orci, L., Unger, R. H. & Scherer, P. E. Diabetes and apoptosis: lipotoxicity. Apoptosis 14, 1484–1495 (2009).
  CAS PubMed Google Scholar
• Scherer, P. E. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 55, 1537–1545 (2006). This paper highlights the various functions of adipose tissue.
  CAS PubMed Google Scholar
• Sun, K., Kusminski, C. M. & Scherer, P. E. Adipose tissue remodeling and obesity. J. Clin. Invest. 121, 2094–2101 (2011). A review article summarizing the key steps leading to adipose tissue dysfunction.
  CAS PubMed PubMed Central Google Scholar
• Unger, R. H. & Scherer, P. E. Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Trends Endocrinol. Metab. 21, 345–352 (2010).
  CAS PubMed PubMed Central Google Scholar
• Kusminski, C. M. & Scherer, P. E. Mitochondrial dysfunction in white adipose tissue. Trends Endocrinol. Metab. 23, 435–443 (2012).
  CAS PubMed PubMed Central Google Scholar
• Sun, K., Tordjman, J., Clement, K. & Scherer, P. E. Fibrosis and adipose tissue dysfunction. Cell Metab. 18, 470–477 (2013).
  CAS PubMed PubMed Central Google Scholar
• Rosen, E. D. & Spiegelman, B. M. What we talk about when we talk about fat. Cell 156, 20–44 (2014). An excellent overview of the current knowledge of adipose tissue physiology.
  CAS PubMed PubMed Central Google Scholar
• Rutkowski, J. M., Stern, J. H. & Scherer, P. E. The cell biology of fat expansion. J. Cell Biol. 208, 501–512 (2015).
  CAS PubMed PubMed Central Google Scholar
• Frayn, K. N., Karpe, F., Fielding, B. A., Macdonald, I. A. & Coppack, S. W. Integrative physiology of human adipose tissue. Int. J. Obes. Relat. Metab. Disord. 27, 875–888 (2003).
  CAS PubMed Google Scholar
• Lee, M. J., Wu, Y. & Fried, S. K. Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol. Aspects Med. 34, 1–11 (2013).
  CAS PubMed Google Scholar
• Tchkonia, T. et al. Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab. 17, 644–656 (2013).
  CAS PubMed PubMed Central Google Scholar
• Tchkonia, T. et al. Identification of depot-specific human fat cell progenitors through distinct expression profiles and developmental gene patterns. Am. J. Physiol. Endocrinol. Metab. 292, E298–E307 (2007).
  CAS PubMed Google Scholar
• Cawthorn, W. P., Scheller, E. L. & MacDougald, O. A. Adipose tissue stem cells meet preadipocyte commitment: going back to the future. J. Lipid Res. 53, 227–246 (2012).
  CAS PubMed PubMed Central Google Scholar
• Staszkiewicz, J., Gimble, J. M., Manuel, J. A. & Gawronska-Kozak, B. IFATS collection: stem cell antigen-1-positive ear mesenchymal stem cells display enhanced adipogenic potential. Stem Cells 26, 2666–2673 (2008).
  CAS PubMed PubMed Central Google Scholar
• Rosen, E. D. & Spiegelman, B. M. PPARγ: a nuclear regulator of metabolism, differentiation, and cell growth. J. Biol. Chem. 276, 37731–37734 (2001).
  CAS PubMed Google Scholar
• Farmer, S. R. Transcriptional control of adipocyte formation. Cell Metab. 4, 263–273 (2006). A concise summary of the key steps controlling adipogenesis.
  CAS PubMed PubMed Central Google Scholar
• Tontonoz, P. & Spiegelman, B. M. Fat and beyond: the diverse biology of PPARγ. Annu. Rev. Biochem. 77, 289–312 (2008).
  CAS PubMed Google Scholar
• Altiok, S., Xu, M. & Spiegelman, B. M. PPARγ induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A. Genes Dev. 11, 1987–1998 (1997).
  CAS PubMed PubMed Central Google Scholar
• Tontonoz, P., Hu, E. & Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79, 1147–1156 (1994).
  CAS PubMed Google Scholar
• Wang, Q. A. et al. Distinct regulatory mechanisms governing embryonic versus adult adipocyte maturation. Nat. Cell Biol. 17, 1099–1111 (2015). A recent mechanistic study addressing the transcriptional requirements at various stages of adipogenesis in vivo.
  CAS PubMed PubMed Central Google Scholar
• Gupta, R. K. et al. Transcriptional control of preadipocyte determination by Zfp423. Nature 464, 619–623 (2010).
  CAS PubMed PubMed Central Google Scholar
• Vishvanath, L. et al. Pdgfrβ+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice. Cell Metab. 23, 350–359 (2015). This paper describes adipogenic precursors and their contribution to fat expansion.
  PubMed PubMed Central Google Scholar
• Spalding, K. L. et al. Dynamics of fat cell turnover in humans. Nature 453, 783–787 (2008).
  CAS PubMed Google Scholar
• Fasshauer, M. & Bluher, M. Adipokines in health and disease. Trends Pharmacol. Sci. 36, 461–470 (2015).
  CAS PubMed Google Scholar
• Holland, W. L. & Summers, S. A. Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr. Rev. 29, 381–402 (2008).
  CAS PubMed PubMed Central Google Scholar
• Flier, J. S., Cook, K. S., Usher, P. & Spiegelman, B. M. Severely impaired adipsin expression in genetic and acquired obesity. Science 237, 405–408 (1987).
  CAS PubMed Google Scholar
• Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).
  CAS PubMed Google Scholar
• Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
  CAS PubMed Google Scholar
• Scherer, P. E., Williams, S., Fogliano, M., Baldini, G. & Lodish, H. F. A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749 (1995). The first report describing adiponectin.
  CAS PubMed Google Scholar
• Friedman, J. 20 years of leptin: leptin at 20: an overview. J. Endocrinol. 223, T1–T8 (2014).
  CAS PubMed Google Scholar
• Farooqi, I. S. & O'Rahilly, S. Leptin: a pivotal regulator of human energy homeostasis. Am. J. Clin. Nutr. 89, 980S–984S (2009).
  CAS PubMed Google Scholar
• Williams, K. W. & Elmquist, J. K. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat. Neurosci. 15, 1350–1355 (2012).
  CAS PubMed PubMed Central Google Scholar
• Kusminski, C. M. & Scherer, P. E. Leptin beyond the lipostat: key component of blood pressure regulation. Circ. Res. 116, 1293–1295 (2015).
  CAS PubMed PubMed Central Google Scholar
• Ye, R. & Scherer, P. E. Adiponectin, driver or passenger on the road to insulin sensitivity? Mol. Metab. 2, 133–141 (2013).
  CAS PubMed PubMed Central Google Scholar
• Shetty, S., Kusminski, C. M. & Scherer, P. E. Adiponectin in health and disease: evaluation of adiponectin-targeted drug development strategies. Trends Pharmacol. Sci. 30, 234–239 (2009).
  CAS PubMed Google Scholar
• Pajvani, U. B. et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J. Biol. Chem. 279, 12152–12162 (2004).
  CAS PubMed Google Scholar
• Turer, A. T. & Scherer, P. E. Adiponectin: mechanistic insights and clinical implications. Diabetologia 55, 2319–2326 (2012).
  CAS PubMed Google Scholar
• Yamauchi, T. et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423, 762–769 (2003). An important paper describing the cloning of adiponectin receptors.
  CAS PubMed Google Scholar
• Holland, W. L. et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat. Med. 17, 55–63 (2011). A report highlighting the connection between adiponectin and sphingolipid metabolism.
  CAS PubMed Google Scholar
• Hug, C. et al. T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. Proc. Natl Acad. Sci. USA 101, 10308–10313 (2004).
  CAS PubMed PubMed Central Google Scholar
• Denzel, M. S. et al. T-cadherin is critical for adiponectin-mediated cardioprotection in mice. J. Clin. Invest. 120, 4342–4352 (2010).
  CAS PubMed PubMed Central Google Scholar
• Matsuda, K. et al. Positive feedback regulation between adiponectin and T-cadherin impacts adiponectin levels in tissue and plasma of male mice. Endocrinology 156, 934–946 (2015).
  CAS PubMed Google Scholar
• Hui, X. et al. Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation. Cell Metab. 22, 279–290 (2015).
  CAS PubMed Google Scholar
• Hotta, K. et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler. Thromb. Vasc. Biol. 20, 1595–1599 (2000).
  CAS PubMed Google Scholar
• Turer, A. T. et al. Adipose tissue mass and location affect circulating adiponectin levels. Diabetologia 54, 2515–2524 (2011).
  CAS PubMed PubMed Central Google Scholar
• Combs, T. P. et al. A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology 145, 367–383 (2004).
  CAS PubMed Google Scholar
• Yamauchi, T. et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 7, 941–946 (2001).
  CAS PubMed Google Scholar
• Berg, A. H., Combs, T. P., Du, X., Brownlee, M. & Scherer, P. E. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat. Med. 7, 947–953 (2001). References 48 and 49 provide the initial description of the effects of recombinant adiponectin.
  CAS PubMed Google Scholar
• Iwabu, M. et al. Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1. Nature 464, 1313–1319 (2010).
  CAS PubMed Google Scholar
• Okamoto, M. et al. Adiponectin induces insulin secretion in vitro and in vivo at a low glucose concentration. Diabetologia 51, 827–835 (2008).
  CAS PubMed Google Scholar
• Kim, C. H. et al. MKR mice are resistant to the metabolic actions of both insulin and adiponectin: discordance between insulin resistance and adiponectin responsiveness. Am. J. Physiol. Endocrinol. Metab. 291, E298–E305 (2006).
  CAS PubMed Google Scholar
• Li, R., Lau, W. B. & Ma, X. L. Adiponectin resistance and vascular dysfunction in the hyperlipidemic state. Acta Pharmacol. Sin. 31, 1258–1266 (2010).
  CAS PubMed PubMed Central Google Scholar
• Kim, J. Y. et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J. Clin. Invest. 117, 2621–2637 (2007).
  CAS PubMed PubMed Central Google Scholar
• Prins, J. B. & O'Rahilly, S. Regulation of adipose cell number in man. Clin. Sci. (Lond.) 92, 3–11 (1997).
  CAS Google Scholar
• Wang, Q. A., Tao, C., Gupta, R. K. & Scherer, P. E. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat. Med. 19, 1338–1344 (2013). A methodological paper describing the tracing of new mature adipocytes.
  PubMed PubMed Central Google Scholar
• Tchoukalova, Y. D. et al. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Proc. Natl Acad. Sci. USA 107, 18226–18231 (2010).
  CAS PubMed PubMed Central Google Scholar
• Ryden, M. et al. Transplanted bone marrow-derived cells contribute to human adipogenesis. Cell Metab. 22, 408–417 (2015).
  CAS PubMed Google Scholar
• Lackey, D. E. & Olefsky, J. M. Regulation of metabolism by the innate immune system. Nat. Rev. Endocrinol. 12, 15–28 (2016).
  CAS PubMed Google Scholar
• Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).
  CAS PubMed PubMed Central Google Scholar
• Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).
  CAS PubMed PubMed Central Google Scholar
• Lumeng, C. N., Bodzin, J. L. & Saltiel, A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).
  CAS PubMed PubMed Central Google Scholar
• Patsouris, D. et al. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 8, 301–309 (2008).
  CAS PubMed PubMed Central Google Scholar
• Cinti, S. et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46, 2347–2355 (2005).
  CAS PubMed Google Scholar
• Wernstedt Asterholm, I. et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab. 20, 103–118 (2014). This paper establishes the metabolically beneficial effects of inflammation in adipose tissue.
  CAS PubMed Google Scholar
• Ricard-Blum, S. The collagen family. Cold Spring Harb. Perspect. Biol. 3, a004978 (2011).
  PubMed PubMed Central Google Scholar
• Iyengar, P. et al. Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. J. Clin. Invest. 115, 1163–1176 (2005).
  CAS PubMed PubMed Central Google Scholar
• Khan, T. et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29, 1575–1591 (2009).
  CAS PubMed Google Scholar
• Trayhurn, P. Hypoxia and adipocyte physiology: implications for adipose tissue dysfunction in obesity. Annu. Rev. Nutr. 34, 207–236 (2014).
  CAS PubMed Google Scholar
• Krishnan, J. et al. Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2–NAD+ system. Genes Dev. 26, 259–270 (2012).
  CAS PubMed PubMed Central Google Scholar
• Halberg, N. et al. Hypoxia-inducible factor 1α induces fibrosis and insulin resistance in white adipose tissue. Mol. Cell. Biol. 29, 4467–4483 (2009). This paper describes the phenomenon of hypoxic conditions in adipose tissue.
  CAS PubMed PubMed Central Google Scholar
• Sun, K., Halberg, N., Khan, M., Magalang, U. J. & Scherer, P. E. Selective inhibition of hypoxia-inducible factor 1α ameliorates adipose tissue dysfunction. Mol. Cell. Biol. 33, 904–917 (2013).
  CAS PubMed PubMed Central Google Scholar
• Colberg, S. R. et al. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement. Diabetes Care 33, e147–e167 (2010).
  PubMed PubMed Central Google Scholar
• Knowler, W. C. et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).
  CAS PubMed Google Scholar
• Linden, M. A., Pincu, Y., Martin, S. A., Woods, J. A. & Baynard, T. Moderate exercise training provides modest protection against adipose tissue inflammatory gene expression in response to high-fat feeding. Physiol. Rep. 2, e12071 (2014).
  PubMed PubMed Central Google Scholar
• Reinehr, T. Lifestyle intervention in childhood obesity: changes and challenges. Nat. Rev. Endocrinol. 9, 607–614 (2013).
  PubMed Google Scholar
• Stanford, K. I. et al. A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis. Diabetes 64, 2002–2014 (2015).
  CAS PubMed PubMed Central Google Scholar
• Guh, D. P. et al. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Publ. Health 9, 88 (2009).
  Google Scholar
• American Diabetes Association. 6. Obesity management for the treatment of type 2 diabetes. Diabetes Care 39 (Suppl. 1), S47–S51 (2016).
• Astrup, A. et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int. J. Obes (Lond.) 36, 843–854 (2012).
  CAS Google Scholar
• Pi-Sunyer, X. et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N. Engl. J. Med. 373, 11–22 (2015).
  PubMed Google Scholar
• Sumithran, P. & Proietto, J. Benefit–risk assessment of orlistat in the treatment of obesity. Drug Saf. 37, 597–608 (2014).
  CAS PubMed Google Scholar
• Smith, S. R. et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N. Engl. J. Med. 363, 245–256 (2010).
  CAS PubMed Google Scholar
• Verrotti, A. et al. Topiramate-induced weight loss: a review. Epilepsy Res. 95, 189–199 (2011).
  CAS PubMed Google Scholar
• Greenway, F. L. et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 376, 595–605 (2010).
  CAS PubMed Google Scholar
• Ornellas, T. & Chavez, B. Naltrexone SR/bupropion SR (contrave): a new approach to weight loss in obese adults. P T 36, 255–262 (2011).
  PubMed PubMed Central Google Scholar
• Ismail-Beigi, F. et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 376, 419–430 (2010).
  PubMed PubMed Central Google Scholar
• [No authors listed.] Introduction. Diabetes Care 39 (Suppl. 1), S1–S2 (2016).
• Pryor, R. & Cabreiro, F. Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem. J. 471, 307–322 (2015).
  CAS PubMed Google Scholar
• Turner, R. C., Cull, C. A., Frighi, V. & Holman, R. R. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 281, 2005–2012 (1999).
  CAS PubMed Google Scholar
• Drucker, D. J. & Nauck, M. A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368, 1696–1705 (2006).
  CAS PubMed Google Scholar
• Amori, R. E., Lau, J. & Pittas, A. G. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 298, 194–206 (2007).
  CAS PubMed Google Scholar
• Yki-Jarvinen, H. Thiazolidinediones. N. Engl. J. Med. 351, 1106–1118 (2004).
  PubMed Google Scholar
• Nawrocki, A. R. et al. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor γ agonists. J. Biol. Chem. 281, 2654–2660 (2006).
  CAS PubMed Google Scholar
• Zhang, Q., Dou, J. & Lu, J. Combinational therapy with metformin and sodium-glucose cotransporter inhibitors in management of type 2 diabetes: systematic review and meta-analyses. Diabetes Res. Clin. Pract. 105, 313–321 (2014).
  CAS PubMed Google Scholar
• Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117–2128 (2015). A recent landmark study highlighting the cardioprotective effects of an SGLT2 inhibitor.
  CAS PubMed Google Scholar
• Phillippe, H. M. & Wargo, K. A. Mitiglinide: a novel agent for the treatment of type 2 diabetes mellitus. Ann. Pharmacother. 44, 1615–1623 (2010).
  PubMed Google Scholar
• Mulvihill, E. E. & Drucker, D. J. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr. Rev. 35, 992–1019 (2014).
  CAS PubMed Google Scholar
• DiNicolantonio, J. J., Bhutani, J. & O'Keefe, J. H. Acarbose: safe and effective for lowering postprandial hyperglycaemia and improving cardiovascular outcomes. Open Heart 2, e000327 (2015).
  PubMed PubMed Central Google Scholar
• DeFronzo, R. A., Davidson, J. A. & Del Prato, S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes. Metab. 14, 5–14 (2012).
  CAS PubMed Google Scholar
• Finan, B. et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med. 5, 209ra151 (2013).
  PubMed Google Scholar
• Finan, B. et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21, 27–36 (2015).
  CAS PubMed Google Scholar
• Challa, T. D. et al. Regulation of adipocyte formation by GLP-1/GLP-1R signaling. J. Biol. Chem. 287, 6421–6430 (2012).
  CAS PubMed Google Scholar
• Shao, Y., Yuan, G., Zhang, J. & Guo, X. Liraglutide reduces lipogenetic signals in visceral adipose of db/db mice with AMPK activation and Akt suppression. Drug Des. Devel. Ther. 9, 1177–1184 (2015).
  CAS PubMed PubMed Central Google Scholar
• Topol, E. J. et al. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet 376, 517–523 (2010).
  CAS PubMed Google Scholar
• Lehr, S., Hartwig, S. & Sell, H. Adipokines: a treasure trove for the discovery of biomarkers for metabolic disorders. Proteom. Clin. Appl. 6, 91–101 (2012).
  CAS Google Scholar
• Dahlman, I. et al. Functional annotation of the human fat cell secretome. Arch. Physiol. Biochem. 118, 84–91 (2012).
  CAS PubMed Google Scholar
• Ahima, R. S., Saper, C. B., Flier, J. S. & Elmquist, J. K. Leptin regulation of neuroendocrine systems. Front. Neuroendocrinol. 21, 263–307 (2000).
  CAS PubMed Google Scholar
• Myers, M. G. Jr et al. Challenges and opportunities of defining clinical leptin resistance. Cell Metab. 15, 150–156 (2012).
  CAS PubMed PubMed Central Google Scholar
• Heymsfield, S. B. et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282, 1568–1575 (1999).
  CAS PubMed Google Scholar
• Mittendorfer, B. et al. Recombinant human leptin treatment does not improve insulin action in obese subjects with type 2 diabetes. Diabetes 60, 1474–1477 (2011).
  CAS PubMed PubMed Central Google Scholar
• Hukshorn, C. J. et al. Weekly subcutaneous pegylated recombinant native human leptin (PEG-OB) administration in obese men. J. Clin. Endocrinol. Metab. 85, 4003–4009 (2000).
  CAS PubMed Google Scholar
• Hoffmann, A. et al. Leptin dose-dependently decreases atherosclerosis by attenuation of hypercholesterolemia and induction of adiponectin. Biochim. Biophys. Acta 1862, 113–120 (2015).
  PubMed Google Scholar
• Dodd, G. T. et al. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160, 88–104 (2015).
  CAS PubMed PubMed Central Google Scholar
• Farooqi, I. S. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341, 879–884 (1999). This study established the effects of recombinant leptin in human leptin deficiency.
  CAS PubMed Google Scholar
• Akinci, G. & Akinci, B. Metreleptin treatment in patients with non-HIV associated lipodystrophy. Recent Pat. Endocr. Metab. Immune Drug Discov. 9, 74–78 (2015).
  CAS PubMed Google Scholar
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT00673387 (2008).
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT01235741 (2010).
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT00265980 (2005).
• Kissileff, H. R. et al. Leptin reverses declines in satiation in weight-reduced obese humans. Am. J. Clin. Nutr. 95, 309–317 (2012).
  CAS PubMed PubMed Central Google Scholar
• Rosenbaum, M. & Leibel, R. L. 20 years of leptin: role of leptin in energy homeostasis in humans. J. Endocrinol. 223, T83–T96 (2014).
  CAS PubMed PubMed Central Google Scholar
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT00085982 (2004).
• Oral, E. A. et al. Leptin-replacement therapy for lipodystrophy. N. Engl. J. Med. 346, 570–578 (2002).
  CAS PubMed Google Scholar
• Ogawa, A., Harris, V., McCorkle, S. K., Unger, R. H. & Luskey, K. L. Amylin secretion from the rat pancreas and its selective loss after streptozotocin treatment. J. Clin. Invest. 85, 973–976 (1990).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Wang, M. Y. et al. Leptin therapy in insulin-deficient type I diabetes. Proc. Natl Acad. Sci. USA 107, 4813–4819 (2010).
  CAS PubMed PubMed Central Google Scholar
• Unger, R. H. & Roth, M. G. A new biology of diabetes revealed by leptin. Cell Metab. 21, 15–20 (2015).
  CAS PubMed Google Scholar
• Shimabukuro, M., Zhou, Y. T., Levi, M. & Unger, R. H. Fatty acid-induced β cell apoptosis: a link between obesity and diabetes. Proc. Natl Acad. Sci. USA 95, 2498–2502 (1998).
  CAS PubMed PubMed Central Google Scholar
• Shpilman, M. et al. Development and characterization of high affinity leptins and leptin antagonists. J. Biol. Chem. 286, 4429–4442 (2011).
  CAS PubMed Google Scholar
• Elinav, E. et al. Pegylated leptin antagonist is a potent orexigenic agent: preparation and mechanism of activity. Endocrinology 150, 3083–3091 (2009).
  CAS PubMed PubMed Central Google Scholar
• Kadowaki, T., Yamauchi, T. & Kubota, N. The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. FEBS Lett. 582, 74–80 (2008).
  CAS PubMed Google Scholar
• Holland, W. L. et al. An FGF21–adiponectin–ceramide axis controls energy expenditure and insulin action in mice. Cell Metab. 17, 790–797 (2013).
  CAS PubMed PubMed Central Google Scholar
• Xia, J. Y. et al. Targeted induction of ceramide degradation leads to improved systemic metabolism and reduced hepatic steatosis. Cell Metab. 22, 266–278 (2015). This study describes the first inducible mouse model for testing the acute effects of ceramide depletion on insulin sensitivity.
  CAS PubMed PubMed Central Google Scholar
• Asterholm, I. W. & Scherer, P. E. Enhanced metabolic flexibility associated with elevated adiponectin levels. Am. J. Pathol. 176, 1364–1376 (2010).
  CAS PubMed PubMed Central Google Scholar
• Halberg, N. et al. Systemic fate of the adipocyte-derived factor adiponectin. Diabetes 58, 1961–1970 (2009).
  PubMed PubMed Central Google Scholar
• Okada-Iwabu, M. et al. A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503, 493–499 (2013).
  CAS PubMed Google Scholar
• Tanabe, H. et al. Crystal structures of the human adiponectin receptors. Nature 520, 312–316 (2015). A major breakthrough reporting the high resolution structure of adiponectin receptors.
  CAS PubMed PubMed Central Google Scholar
• Ealey, K. N., Kaludjerovic, J., Archer, M. C. & Ward, W. E. Adiponectin is a negative regulator of bone mineral and bone strength in growing mice. Exp. Biol. Med. (Maywood) 233, 1546–1553 (2008).
  CAS Google Scholar
• Yore, M. M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014).
  CAS PubMed PubMed Central Google Scholar
• Markan, K. R. et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 63, 4057–4063 (2014).
  CAS PubMed PubMed Central Google Scholar
• Owen, B. M., Mangelsdorf, D. J. & Kliewer, S. A. Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol. Metab. 26, 22–29 (2015). An excellent summary of the actions of FGF19 and FGF21.
  CAS PubMed Google Scholar
• Kliewer, S. A. & Mangelsdorf, D. J. Fibroblast growth factor 21: from pharmacology to physiology. Am. J. Clin. Nutr. 91, 254S–257S (2010).
  CAS PubMed Google Scholar
• Ding, X. et al. βklotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab. 16, 387–393 (2012).
  CAS PubMed PubMed Central Google Scholar
• Fisher, F. M. & Maratos-Flier, E. Understanding the physiology of FGF21. Annu. Rev. Physiol. 10, 223–241 (2015).
  Google Scholar
• Xu, J. et al. Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models — association with liver and adipose tissue effects. Am. J. Physiol. Endocrinol. Metab. 297, E1105–E1114 (2009).
  CAS PubMed Google Scholar
• Coskun, T. et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149, 6018–6027 (2008).
  CAS PubMed Google Scholar
• Kharitonenkov, A. et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148, 774–781 (2007).
  CAS PubMed Google Scholar
• Fisher, F. M. et al. Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology 147, 1073–1083.e6 (2014).
  CAS PubMed Google Scholar
• Owen, B. M. et al. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab. 20, 670–677 (2014).
  CAS PubMed PubMed Central Google Scholar
• Talukdar, S. et al. FGF21 regulates sweet and alcohol preference. Cell Metab. 23, 344–349 (2015).
  PubMed PubMed Central Google Scholar
• Adams, A. C. et al. The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue. Mol. Metab. 2, 31–37 (2012).
  CAS PubMed PubMed Central Google Scholar
• Lin, Z. et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab. 17, 779–789 (2013).
  CAS PubMed Google Scholar
• Fisher, F. M. et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26, 271–281 (2012).
  CAS PubMed PubMed Central Google Scholar
• Gimeno, R. E. & Moller, D. E. FGF21-based pharmacotherapy — potential utility for metabolic disorders. Trends Endocrinol. Metab. 25, 303–311 (2014).
  CAS PubMed Google Scholar
• Gaich, G. et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 18, 333–340 (2013).
  CAS PubMed Google Scholar
• Dong, J. Q. et al. Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study. Br. J. Clin. Pharmacol. 80, 1051–1063 (2015).
  CAS PubMed PubMed Central Google Scholar
• Kharitonenkov, A. et al. Rational design of a fibroblast growth factor 21-based clinical candidate, LY2405319. PLoS ONE 8, e58575 (2013).
  CAS PubMed PubMed Central Google Scholar
• Adams, A. C. et al. LY2405319, an engineered FGF21 variant, improves the metabolic status of diabetic monkeys. PLoS ONE 8, e65763 (2013).
  CAS PubMed PubMed Central Google Scholar
• Kim, J. H. et al. Fibroblast growth factor 21 analogue LY2405319 lowers blood glucose in streptozotocin-induced insulin-deficient diabetic mice by restoring brown adipose tissue function. Diabetes Obes. Metab. 17, 161–169 (2015).
  CAS PubMed Google Scholar
• Talukdar, S. et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427–440 (2016).
  CAS PubMed Google Scholar
• Weng, Y. et al. Pharmacokinetics (PK), pharmacodynamics (PD) and integrated PK/PD modeling of a novel long acting FGF21 clinical candidate PF-05231023 in diet-induced obese and leptin-deficient obese mice. PLoS ONE 10, e0119104 (2015).
  PubMed PubMed Central Google Scholar
• Wu, S., Levenson, A., Kharitonenkov, A. & De Luca, F. Fibroblast growth factor 21 (FGF21) inhibits chondrocyte function and growth hormone action directly at the growth plate. J. Biol. Chem. 287, 26060–26067 (2012).
  CAS PubMed PubMed Central Google Scholar
• Wei, W. et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. Proc. Natl Acad. Sci. USA 109, 3143–3148 (2012).
  CAS PubMed PubMed Central Google Scholar
• Owen, B. M. et al. FGF21 contributes to neuroendocrine control of female reproduction. Nat. Med. 19, 1153–1156 (2013).
  CAS PubMed PubMed Central Google Scholar
• Bookout, A. L. et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat. Med. 19, 1147–1152 (2013).
  CAS PubMed PubMed Central Google Scholar
• Lee, P. et al. Fibroblast growth factor 21 (FGF21) and bone: is there a relationship in humans? Osteoporos. Int. 24, 3053–3057 (2013).
  CAS PubMed PubMed Central Google Scholar
• Tseng, Y. H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008).
  CAS PubMed PubMed Central Google Scholar
• Townsend, K. L. et al. Bone morphogenetic protein 7 (BMP7) reverses obesity and regulates appetite through a central mTOR pathway. FASEB J. 26, 2187–2196 (2012).
  CAS PubMed PubMed Central Google Scholar
• Zeng, J., Jiang, Y., Xiang, S. & Chen, B. Serum bone morphogenetic protein 7, insulin resistance, and insulin secretion in non-diabetic individuals. Diabetes Res. Clin. Pract. 93, e21–e24 (2011).
  CAS PubMed Google Scholar
• Vaccaro, A. R. et al. The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for posterolateral lumbar arthrodesis: minimum 4-year follow-up of a pilot study. Spine J. 8, 457–465 (2008).
  PubMed Google Scholar
• Bing, C. Is interleukin-1β a culprit in macrophage-adipocyte crosstalk in obesity? Adipocyte 4, 149–152 (2015).
  CAS PubMed PubMed Central Google Scholar
• Gao, D. et al. Interleukin-1β mediates macrophage-induced impairment of insulin signaling in human primary adipocytes. Am. J. Physiol. Endocrinol. Metab. 307, E289–E304 (2014).
  CAS PubMed PubMed Central Google Scholar
• Handa, M. et al. XOMA 052, an anti-IL-1β monoclonal antibody, prevents IL-1β-mediated insulin resistance in 3T3-L1 adipocytes. Obesity (Silver Spring) 21, 306–309 (2013).
  CAS Google Scholar
• Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).
  CAS PubMed Google Scholar
• van Asseldonk, E. J. et al. One week treatment with the IL-1 receptor antagonist anakinra leads to a sustained improvement in insulin sensitivity in insulin resistant patients with type 1 diabetes mellitus. Clin. Immunol. 160, 155–162 (2015).
  CAS PubMed Google Scholar
• Rissanen, A., Howard, C. P., Botha, J., Thuren, T. & Global, I. Effect of anti-IL-1β antibody (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes: results of a randomized, placebo-controlled trial. Diabetes Obes. Metab. 14, 1088–1096 (2012).
  CAS PubMed Google Scholar
• Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
  CAS PubMed Google Scholar
• Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).
  CAS PubMed PubMed Central Google Scholar
• Heaton, J. M. The distribution of brown adipose tissue in the human. J. Anat. 112, 35–39 (1972).
  CAS PubMed PubMed Central Google Scholar
• Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).
  CAS PubMed PubMed Central Google Scholar
• van Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009). References 180 and 181 establish the presence of brown adipose tissue in adult humans.
  CAS PubMed Google Scholar
• Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).
  CAS PubMed Google Scholar
• Flynn, A. et al. Contrast-enhanced ultrasound: a novel noninvasive, nonionizing method for the detection of brown adipose tissue in humans. J. Am. Soc. Echocardiogr. 28, 1247–1254 (2015).
  PubMed PubMed Central Google Scholar
• Peirce, V., Carobbio, S. & Vidal-Puig, A. The different shades of fat. Nature 510, 76–83 (2014).
  CAS PubMed Google Scholar
• Stock, M. J. & Rothwell, N. J. Role of brown adipose tissue thermogenesis in overfeeding: a review. J. R. Soc. Med. 76, 71–73 (1983).
  CAS PubMed PubMed Central Google Scholar
• Nedergaard, J., Bengtsson, T. & Cannon, B. Three years with adult human brown adipose tissue. Ann. NY Acad. Sci. 1212, E20–E36 (2010).
  PubMed Google Scholar
• Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).
  CAS PubMed Google Scholar
• Peirce, V. & Vidal-Puig, A. Regulation of glucose homoeostasis by brown adipose tissue. Lancet Diabetes Endocrinol. 1, 353–360 (2013).
  CAS PubMed Google Scholar
• Geerling, J. J. et al. Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice. Diabetes 63, 880–891 (2014).
  CAS PubMed Google Scholar
• Baxter, J. D. & Webb, P. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat. Rev. Drug Discov. 8, 308–320 (2009).
  CAS PubMed Google Scholar
• Blondin, D. P. et al. Increased brown adipose tissue oxidative capacity in cold-acclimated humans. J. Clin. Endocrinol. Metab. 99, E438–E446 (2014).
  CAS PubMed PubMed Central Google Scholar
• Yoneshiro, T. et al. Recruited brown adipose tissue as an antiobesity agent in humans. J. Clin. Invest. 123, 3404–3408 (2013).
  CAS PubMed PubMed Central Google Scholar
• Chen, K. Y. et al. Brown fat activation mediates cold-induced thermogenesis in adult humans in response to a mild decrease in ambient temperature. J. Clin. Endocrinol. Metab. 98, E1218–E1223 (2013).
  CAS PubMed PubMed Central Google Scholar
• Matsushita, M. et al. Impact of brown adipose tissue on body fatness and glucose metabolism in healthy humans. Int. J. Obes. (Lond.) 38, 812–817 (2014).
  CAS Google Scholar
• Chondronikola, M. et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 63, 4089–4099 (2014).
  CAS PubMed PubMed Central Google Scholar
• Orava, J. et al. Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans. Obesity (Silver Spring) 21, 2279–2287 (2013).
  CAS Google Scholar
• Whittle, A., Relat-Pardo, J. & Vidal-Puig, A. Pharmacological strategies for targeting BAT thermogenesis. Trends Pharmacol. Sci. 34, 347–355 (2013).
  CAS PubMed Google Scholar
• Ghorbani, M. & Himms-Hagen, J. Appearance of brown adipocytes in white adipose tissue during CL 316,243-induced reversal of obesity and diabetes in Zucker fa/fa rats. Int. J. Obes Relat. Metab. Disord. 21, 465–475 (1997).
  CAS PubMed Google Scholar
• Cypess, A. M. et al. Cold but not sympathomimetics activates human brown adipose tissue in vivo. Proc. Natl Acad. Sci. USA 109, 10001–10005 (2012).
  CAS PubMed PubMed Central Google Scholar
• Vosselman, M. J. et al. Systemic β-adrenergic stimulation of thermogenesis is not accompanied by brown adipose tissue activity in humans. Diabetes 61, 3106–3113 (2012).
  CAS PubMed PubMed Central Google Scholar
• Carey, A. L. et al. Ephedrine activates brown adipose tissue in lean but not obese humans. Diabetologia 56, 147–155 (2013).
  CAS PubMed Google Scholar
• Cypess, A. M. et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 21, 33–38 (2015). An elegant study reporting the ability to stimulate the activity of human BAT.
  CAS PubMed PubMed Central Google Scholar
• Colman, E. Dinitrophenol and obesity: an early twentieth-century regulatory dilemma. Regul. Toxicol. Pharmacol. 48, 115–117 (2007).
  CAS PubMed Google Scholar
• Perry, R. J. et al. Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metab. 18, 740–748 (2013).
  CAS PubMed PubMed Central Google Scholar
• Perry, R. J., Zhang, D., Zhang, X. M., Boyer, J. L. & Shulman, G. I. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science 347, 1253–1256 (2015).
  CAS PubMed PubMed Central Google Scholar
• Bostrom, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).
  PubMed PubMed Central Google Scholar
• Albrecht, E. et al. Irisin — a myth rather than an exercise-inducible myokine. Sci. Rep. 5, 8889 (2015).
  CAS PubMed PubMed Central Google Scholar
• Raschke, S. et al. Evidence against a beneficial effect of irisin in humans. PLoS ONE 8, e73680 (2013).
  CAS PubMed PubMed Central Google Scholar
• Lee, P. et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 19, 302–309 (2014).
  CAS PubMed PubMed Central Google Scholar
• Jedrychowski, M. P. et al. Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell Metab. 22, 734–740 (2015).
  CAS PubMed PubMed Central Google Scholar
• Rao, R. R. et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157, 1279–1291 (2014).
  CAS PubMed PubMed Central Google Scholar
• Cohen, P. et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156, 304–316 (2014).
  CAS PubMed PubMed Central Google Scholar
• Kong, X. et al. IRF4 is a key thermogenic transcriptional partner of PGC-1α. Cell 158, 69–83 (2014).
  CAS PubMed PubMed Central Google Scholar
• Kazak, L. et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163, 643–655 (2015).
  CAS PubMed PubMed Central Google Scholar
• Whittle, A. J. et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 149, 871–885 (2012).
  CAS PubMed PubMed Central Google Scholar
• Fang, S. et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat. Med. 21, 159–165 (2015).
  CAS PubMed PubMed Central Google Scholar
• Sun, K. et al. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc. Natl Acad. Sci. USA 109, 5874–5879 (2012). This study established the metabolically beneficial effects of expansion of the vasculature in adipose tissue.
  CAS PubMed PubMed Central Google Scholar
• Kusminski, C. M., Park, J. & Scherer, P. E. MitoNEET-mediated effects on browning of white adipose tissue. Nat. Commun. 5, 3962 (2014).
  CAS PubMed Google Scholar
• Qiu, Y. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292–1308 (2014).
  CAS PubMed PubMed Central Google Scholar
• Nguyen, K. D. et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108 (2011).
  CAS PubMed PubMed Central Google Scholar
• Kolumam, G. et al. Sustained brown fat stimulation and insulin sensitization by a humanized bispecific antibody agonist for fibroblast growth factor receptor 1/βklotho complex. eBioMedicine 2, 730–743 (2015).
  PubMed PubMed Central Google Scholar
• Douris, N. et al. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology 156, 2470–2481 (2015).
  CAS PubMed PubMed Central Google Scholar
• Veniant, M. M. et al. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab. 21, 731–738 (2015).
  CAS PubMed Google Scholar
• Samms, R. J. et al. Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. Cell Rep. 11, 991–999 (2015).
  CAS PubMed Google Scholar
• McDonald, M. E. et al. Myocardin-related transcription factor A regulates conversion of progenitors to beige adipocytes. Cell 160, 105–118 (2015).
  CAS PubMed PubMed Central Google Scholar
• Evans, R. M., Barish, G. D. & Wang, Y. X. PPARs and the complex journey to obesity. Nat. Med. 10, 355–361 (2004).
  CAS PubMed Google Scholar
• Choi, J. H. et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5. Nature 466, 451–456 (2010).
  CAS PubMed PubMed Central Google Scholar
• Dhavan, R. & Tsai, L. H. A decade of CDK5. Nat. Rev. Mol. Cell Biol. 2, 749–759 (2001).
  CAS PubMed Google Scholar
• Banks, A. S. et al. An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ. Nature 517, 391–395 (2015).
  CAS PubMed Google Scholar
• Flaherty, K. T. et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 367, 1694–1703 (2012).
  CAS PubMed PubMed Central Google Scholar
• Nemoto, S., Fergusson, M. M. & Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J. Biol. Chem. 280, 16456–16460 (2005).
  CAS PubMed Google Scholar
• Wilson, B. J., Tremblay, A. M., Deblois, G., Sylvain-Drolet, G. & Giguere, V. An acetylation switch modulates the transcriptional activity of estrogen-related receptor α. Mol. Endocrinol. 24, 1349–1358 (2010).
  CAS PubMed PubMed Central Google Scholar
• Picard, F. et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429, 771–776 (2004).
  CAS PubMed PubMed Central Google Scholar
• Mayoral, R. et al. Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity. Mol. Metab. 4, 378–391 (2015).
  CAS PubMed PubMed Central Google Scholar
• Qiang, L. et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ. Cell 150, 620–632 (2012).
  CAS PubMed PubMed Central Google Scholar
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT00920556 (2009).
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT02247596 (2014).
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT01714102 (2012).
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT01038089 (2009).
• Dash, S., Xiao, C., Morgantini, C., Szeto, L. & Lewis, G. F. High-dose resveratrol treatment for 2 weeks inhibits intestinal and hepatic lipoprotein production in overweight/obese men. Arterioscler. Thromb. Vasc. Biol. 33, 2895–2901 (2013).
  CAS PubMed Google Scholar
• Knop, F. K. et al. Thirty days of resveratrol supplementation does not affect postprandial incretin hormone responses, but suppresses postprandial glucagon in obese subjects. Diabet. Med. 30, 1214–1218 (2013).
  CAS PubMed Google Scholar
• Chen, S. et al. Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial. Dig. Liver Dis. 47, 226–232 (2015).
  CAS PubMed Google Scholar
• Brasnyo, P. et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br. J. Nutr. 106, 383–389 (2011).
  CAS PubMed Google Scholar
• Muise, E. S. et al. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor γ and altered metabolic states. Mol. Pharmacol. 74, 403–412 (2008).
  CAS PubMed Google Scholar
• Wang, H., Qiang, L. & Farmer, S. R. Identification of a domain within peroxisome proliferator-activated receptor γ regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Mol. Cell. Biol. 28, 188–200 (2008).
  PubMed Google Scholar
• Dutchak, P. A. et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell 148, 556–567 (2012).
  CAS PubMed PubMed Central Google Scholar
• Wahli, W. & Michalik, L. PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol. Metab. 23, 351–363 (2012).
  CAS PubMed Google Scholar
• Odegaard, J. I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007).
  CAS PubMed PubMed Central Google Scholar
• Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).
  CAS PubMed PubMed Central Google Scholar
• Cipolletta, D. et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012).
  CAS PubMed PubMed Central Google Scholar
• Chiang, S. H. et al. The protein kinase IKKε regulates energy balance in obese mice. Cell 138, 961–975 (2009).
  CAS PubMed PubMed Central Google Scholar
• Ussher, J. R. et al. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 59, 2453–2464 (2010).
  CAS PubMed PubMed Central Google Scholar
• Pedersen, D. J. et al. A major role of insulin in promoting obesity-associated adipose tissue inflammation. Mol. Metab. 4, 507–518 (2015).
  CAS PubMed PubMed Central Google Scholar
• Reilly, S. M. et al. An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice. Nat. Med. 19, 313–321 (2013).
  CAS PubMed PubMed Central Google Scholar
• Makino, H., Saijo, T., Ashida, Y., Kuriki, H. & Maki, Y. Mechanism of action of an antiallergic agent, amlexanox (AA-673), in inhibiting histamine release from mast cells. Acceleration of cAMP generation and inhibition of phosphodiesterase. Int. Arch. Allergy Appl. Immunol. 82, 66–71 (1987).
  CAS PubMed Google Scholar
• Reilly, S. M. et al. A subcutaneous adipose tissue–liver signalling axis controls hepatic gluconeogenesis. Nat. Commun. 6, 6047 (2015).
  CAS PubMed Google Scholar
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT01842282 (2013).
• Stanley, T. L. et al. TNF-α antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J. Clin. Endocrinol. Metab. 96, E146–E150 (2011).
  CAS PubMed Google Scholar
• Dominguez, H. et al. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes. J. Vasc. Res. 42, 517–525 (2005).
  CAS PubMed Google Scholar
• Solomon, D. H. et al. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA 305, 2525–2531 (2011).
  CAS PubMed Google Scholar
• Paquot, N., Castillo, M. J., Lefebvre, P. J. & Scheen, A. J. No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients. J. Clin. Endocrinol. Metab. 85, 1316–1319 (2000).
  CAS PubMed Google Scholar
• Anderson, K., Wherle, L., Park, M., Nelson, K. & Nguyen, L. Salsalate, an old, inexpensive drug with potential new indications: a review of the evidence from 3 recent studies. Am. Health Drug Benefits 7, 231–235 (2014).
  PubMed PubMed Central Google Scholar
• Goldfine, A. B. et al. Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann. Intern. Med. 159, 1–12 (2013).
  PubMed PubMed Central Google Scholar
• Koska, J. et al. The effect of salsalate on insulin action and glucose tolerance in obese non-diabetic patients: results of a randomised double-blind placebo-controlled study. Diabetologia 52, 385–393 (2009).
  CAS PubMed Google Scholar
• Goldfine, A. B. et al. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin. Transl. Sci. 1, 36–43 (2008).
  CAS PubMed PubMed Central Google Scholar
• Barzilay, J. I. et al. The impact of salsalate treatment on serum levels of advanced glycation end products in type 2 diabetes. Diabetes Care 37, 1083–1091 (2014).
  CAS PubMed PubMed Central Google Scholar
• Penesova, A. et al. Salsalate has no effect on insulin secretion but decreases insulin clearance: a randomized, placebo-controlled trial in subjects without diabetes. Diabetes Obes. Metab. 17, 608–612 (2015).
  CAS PubMed Google Scholar
• Raghavan, R. P., Laight, D. W. & Cummings, M. H. Aspirin in type 2 diabetes, a randomised controlled study: effect of different doses on inflammation, oxidative stress, insulin resistance and endothelial function. Int. J. Clin. Pract. 68, 271–277 (2014).
  CAS PubMed Google Scholar
• Oh, D. Y. et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010).
  CAS PubMed PubMed Central Google Scholar
• Oh da, Y. et al. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nat. Med. 20, 942–947 (2014).
  PubMed Google Scholar
• Sullivan, T. J. et al. Experimental evidence for the use of CCR2 antagonists in the treatment of type 2 diabetes. Metabolism 62, 1623–1632 (2013).
  CAS PubMed Google Scholar
• Di Prospero, N. A. et al. CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Diabetes Obes. Metab. 16, 1055–1064 (2014).
  CAS PubMed Google Scholar
• de Zeeuw, D. et al. The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial. Lancet Diabetes Endocrinol. 3, 687–696 (2015).
  CAS PubMed Google Scholar
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT00699790 (2008).
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT01712061 (2012).
• Xue, C. B. et al. Discovery of INCB8761/PF-4136309, a potent, selective, and orally bioavailable CCR2 antagonist. ACS Med. Chem. Lett. 2, 913–918 (2011).
  CAS PubMed PubMed Central Google Scholar
• Filgueiras, L. R., Serezani, C. H. & Jancar, S. Leukotriene B4 as a potential therapeutic target for the treatment of metabolic disorders. Front. Immunol. 6, 515 (2015).
  PubMed PubMed Central Google Scholar
• Li, P. et al. LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nat. Med. 21, 239–247 (2015).
  CAS PubMed PubMed Central Google Scholar
• Liston, T. E. et al. Pharmacokinetics and pharmacodynamics of the leukotriene B4 receptor antagonist CP-105,696 in man following single oral administration. Br. J. Clin. Pharmacol. 45, 115–121 (1998).
  CAS PubMed PubMed Central Google Scholar
• Favalli, E. G. et al. Serious infections during anti-TNFα treatment in rheumatoid arthritis patients. Autoimmun Rev. 8, 266–273 (2009).
  CAS PubMed Google Scholar
• Park, J. & Scherer, P. E. Adipocyte-derived endotrophin promotes malignant tumor progression. J. Clin. Invest. 122, 4243–4256 (2012).
  CAS PubMed PubMed Central Google Scholar
• Sun, K. et al. Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction. Nat. Commun. 5, 3485 (2014).
  PubMed Google Scholar
• Iwayama, T. et al. PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity. Genes Dev. 29, 1106–1119 (2015).
  CAS PubMed PubMed Central Google Scholar
• Haak, A. J. et al. Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury. J. Pharmacol. Exp. Ther. 349, 480–486 (2014).
  PubMed PubMed Central Google Scholar
• Sisson, T. H. et al. Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis. Am. J. Pathol. 185, 969–986 (2015).
  CAS PubMed PubMed Central Google Scholar
• Lee, S. H. et al. ROCK1 isoform-specific deletion reveals a role for diet-induced insulin resistance. Am. J. Physiol. Endocrinol. Metab. 306, E332–E343 (2014).
  CAS PubMed Google Scholar
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT00120718 (2005).
• US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT00498615 (2007).
• Vila, I. K. et al. Immune cell Toll-like receptor 4 mediates the development of obesity- and endotoxemia-associated adipose tissue fibrosis. Cell Rep. 7, 1116–1129 (2014).
  CAS PubMed Google Scholar
• Jia, L. et al. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat. Commun. 5, 3878 (2014).
  CAS PubMed Google Scholar
• Falchook, G. S. et al. Targeting hypoxia-inducible factor-1α (HIF-1α) in combination with antiangiogenic therapy: a phase I trial of bortezomib plus bevacizumab. Oncotarget 5, 10280–10292 (2014).
  PubMed PubMed Central Google Scholar
• Welsh, S., Williams, R., Kirkpatrick, L., Paine-Murrieta, G. & Powis, G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1α. Mol. Cancer Ther. 3, 233–244 (2004).
  CAS PubMed Google Scholar
• Baker, L. C. et al. The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function. Br. J. Cancer 106, 1638–1647 (2012).
  CAS PubMed PubMed Central Google Scholar
• Xia, Y., Choi, H. K. & Lee, K. Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur. J. Med. Chem. 49, 24–40 (2012).
  CAS PubMed Google Scholar
• Montgomery, M. K. & Turner, N. Mitochondrial dysfunction and insulin resistance: an update. Endocr. Connect. 4, R1–R15 (2015).
  PubMed Google Scholar
• Choo, H. J. et al. Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia 49, 784–791 (2006).
  CAS PubMed Google Scholar
• Heinonen, S. et al. Impaired mitochondrial biogenesis in adipose tissue in acquired obesity. Diabetes 64, 3135–3145 (2015).
  CAS PubMed Google Scholar
• Chattopadhyay, M. et al. Enhanced ROS production and oxidative damage in subcutaneous white adipose tissue mitochondria in obese and type 2 diabetes subjects. Mol. Cell. Biochem. 399, 95–103 (2015).
  CAS PubMed Google Scholar
• Wilson-Fritch, L. et al. Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J. Clin. Invest. 114, 1281–1289 (2004).
  CAS PubMed PubMed Central Google Scholar
• Liu, J. et al. Targeting mitochondrial biogenesis for preventing and treating insulin resistance in diabetes and obesity: hope from natural mitochondrial nutrients. Adv. Drug Deliv. Rev. 61, 1343–1352 (2009).
  CAS PubMed Google Scholar
• Armstrong, J. S. Mitochondrial medicine: pharmacological targeting of mitochondria in disease. Br. J. Pharmacol. 151, 1154–1165 (2007).
  CAS PubMed PubMed Central Google Scholar
• Shen, W. et al. _R_-α-lipoic acid and acetyl-L-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes. Diabetologia 51, 165–174 (2008).
  CAS PubMed Google Scholar
• Kusminski, C. M. et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat. Med. 18, 1539–1549 (2012). This study reports the 'heaviest mouse ever'. Despite weighing 129.5 g, these transgenic mice retain full metabolic function.
  CAS PubMed PubMed Central Google Scholar
• Vernochet, C. et al. Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance. Cell Metab. 16, 765–776 (2012).
  CAS PubMed PubMed Central Google Scholar
• McLaughlin, T., Lamendola, C., Liu, A. & Abbasi, F. Preferential fat deposition in subcutaneous versus visceral depots is associated with insulin sensitivity. J. Clin. Endocrinol. Metab. 96, E1756–E1760 (2011).
  CAS PubMed PubMed Central Google Scholar
• Snijder, M. B. et al. Associations of hip and thigh circumferences independent of waist circumference with the incidence of type 2 diabetes: the Hoorn Study. Am. J. Clin. Nutr. 77, 1192–1197 (2003).
  CAS PubMed Google Scholar
• Denis, G. V. & Obin, M. S. 'Metabolically healthy obesity': origins and implications. Mol. Aspects Med. 34, 59–70 (2013).
  CAS PubMed Google Scholar
• Amit, M. et al. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev. Biol. 227, 271–278 (2000).
  CAS PubMed Google Scholar
• Gurtner, G. C., Werner, S., Barrandon, Y. & Longaker, M. T. Wound repair and regeneration. Nature 453, 314–321 (2008).
  CAS PubMed Google Scholar
• Cao, M. et al. Adipose-derived mesenchymal stem cells improve glucose homeostasis in high-fat diet-induced obese mice. Stem Cell Res. Ther. 6, 208 (2015).
  PubMed PubMed Central Google Scholar
• Shang, Q. et al. Delivery of adipose-derived stem cells attenuates adipose tissue inflammation and insulin resistance in obese mice through remodeling macrophage phenotypes. Stem Cells Dev. 24, 2052–2064 (2015).
  CAS PubMed Google Scholar
• Zhang, Q., Liu, L. N., Yong, Q., Deng, J. C. & Cao, W. G. Intralesional injection of adipose-derived stem cells reduces hypertrophic scarring in a rabbit ear model. Stem Cell Res. Ther. 6, 145 (2015).
  PubMed PubMed Central Google Scholar
• Badimon, L., Onate, B. & Vilahur, G. Adipose-derived mesenchymal stem cells and their reparative potential in ischemic heart disease. Rev. Esp. Cardiol. (Engl. Ed) 68, 599–611 (2015).
  Google Scholar