- Zechner, R. et al. FAT SIGNALS—lipases and lipolysis in lipid metabolism and signalling. Cell Metab. 15, 279–291 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Gesta, S., Tseng, Y. H. & Kahn, C. R. Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007).
Article CAS PubMed Google Scholar
- Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
Article CAS PubMed 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).
Article CAS PubMed Google Scholar
- Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).
Article CAS PubMed Google Scholar
- Yoneshiro, T. et al. Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Obesity (Silver Spring) 19, 13–16 (2011).
Article Google Scholar
- Ouellet, V. et al. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. J. Clin. Endocrinol. Metab. 96, 192–199 (2011).
Article CAS PubMed Google Scholar
- van der Lans, A. A. et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J. Clin. Invest. 123, 3395–3403 (2013).
Article 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).
Article CAS PubMed PubMed Central Google Scholar
- Cinti, S. The adipose organ at a glance. Dis. Model. Mech. 5, 588–594 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Klingenspor, M., Herzig, S. & Pfeifer, A. Brown fat develops a brite future. Obes. Facts 5, 890–896 (2012).
Article PubMed Google Scholar
- Nedergaard, J., Bengtsson, T. & Cannon, B. Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444–E452 (2007).
Article CAS PubMed 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).
Article CAS PubMed PubMed Central Google Scholar
- Zingaretti, M. C. et al. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J. 23, 3113–3120 (2009).
Article CAS PubMed Google Scholar
- Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526–1531 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Pfannenberg, C. et al. Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes 59, 1789–1793 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Lowell, B. B. et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366, 740–742 (1993).
Article CAS PubMed Google Scholar
- Enerbäck, S. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–94 (1997).
Article PubMed Google Scholar
- Feldmann, H. M., Golozoubova, V., Cannon, B. & Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 9, 203–209 (2009).
Article CAS PubMed Google Scholar
- Kopecky, J., Clarke, G., Enerbäck, S., Spiegelman, B. & Kozak, L. P. Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J. Clin. Invest 96, 2914–2923 (1995).
Article CAS PubMed PubMed Central Google Scholar
- Van Gaal, L. F., Mertens, I. L. & De Block, C. E. Mechanisms linking obesity with cardiovascular disease. Nature 444, 875–880 (2006).
Article CAS PubMed Google Scholar
- Guilherme, A., Virbasius, J. V., Puri, V. & Czech, M. P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9, 367–377 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Bartelt, A. & Heeren, J. The holy grail of metabolic disease: brown adipose tissue. Curr. Opin. Lipidol. 23, 190–195 (2012).
Article CAS PubMed Google Scholar
- Nedergaard, J. & Cannon, B. How brown is brown fat? It depends where you look. Nat. Med. 19, 540–541 (2013).
Article CAS PubMed Google Scholar
- Timmons, J. A. et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc. Natl Acad. Sci. USA 104, 4401–4406 (2007).
Article CAS PubMed PubMed Central Google Scholar
- Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Tran, K. V. et al. The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells. Cell Metab. 15, 222–229 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Lee, Y. H., Petkova, A. P., Mottillo, E. P. & Granneman, J. G. In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding. Cell Metab. 15, 480–491 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Gupta, R. K. et al. Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab. 15, 230–239 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Petrovic, N. et al. Chronic peroxisome proliferator-activated receptor gamma (PPARγ) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J. Biol. Chem. 285, 7153–7164 (2010).
Article CAS PubMed Google Scholar
- Klaus, S., Ely, M., Encke, D. & Heldmaier, G. Functional assessment of white and brown adipocyte development and energy metabolism in cell culture. Dissociation of terminal differentiation and thermogenesis in brown adipocytes. J. Cell Sci. 108, 3171–3180 (1995).
CAS PubMed Google Scholar
- Schulz, T. J. et al. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc. Natl Acad. Sci. USA 108, 143–148 (2011).
Article 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).
Article CAS PubMed PubMed Central Google Scholar
- Himms-Hagen, J. et al. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am. J. Physiol. Cell Physiol. 279, C670–C681 (2000).
Article CAS PubMed Google Scholar
- Barbatelli, G. et al. The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am. J. Physiol. Endocrinol. Metab. 298, E1244–E1253 (2010).
Article CAS PubMed Google Scholar
- Rosenwald, M., Perdikari, A., Rülicke, T. & Wolfrum, C. Bi-directional interconversion of brite and white adipocytes. Nat. Cell Biol. 15, 659–667 (2013).
Article CAS PubMed Google Scholar
- Sharp, L. Z. et al. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS ONE 7, e49452 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Cypess, A. M. et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat. Med. 19, 635–639 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Jespersen, N. Z. et al. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab. 17, 798–805 (2013).
Article CAS PubMed Google Scholar
- Lidell, M. E. et al. Evidence for two types of brown adipose tissue in humans. Nat. Med. 19, 631–634 (2013).
Article CAS PubMed Google Scholar
- Walden, T. B., Hansen, I. R., Timmons, J. A., Cannon, B. & Nedergaard, J. Recruited vs. nonrecruited molecular signatures of brown, “brite, ” and white adipose tissues. Am. J. Physiol. Endocrinol. Metab. 302, E19–E31 (2012).
Article CAS PubMed Google Scholar
- Farmer, S. R. Transcriptional control of adipocyte formation. Cell Metab. 4, 263–273 (2006).
Article CAS PubMed PubMed Central Google Scholar
- Rosen, E. D. & MacDougald, O. A. Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biol. 7, 885–896 (2006).
Article CAS PubMed Google Scholar
- Linhart, H. G. et al. C/EBPα is required for differentiation of white, but not brown, adipose tissue. Proc. Natl Acad. Sci. USA 98, 12532–12537 (2001).
Article CAS PubMed PubMed Central Google Scholar
- Gesta, S. et al. Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc. Natl Acad. Sci. USA 103, 6676–6681 (2006).
Article CAS PubMed PubMed Central Google Scholar
- Lee, K. Y. et al. Shox2 is a molecular determinant of depot-specific adipocyte function. Proc. Natl Acad. Sci. USA 110, 11409–11414 (2013).
Article PubMed PubMed Central Google Scholar
- Cederberg, A. et al. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 106, 563–573 (2001).
Article CAS PubMed Google Scholar
- Hansen, J. B. et al. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc. Natl Acad. Sci. USA 101, 4112–4117 (2004).
Article CAS PubMed PubMed Central Google Scholar
- Calo, E. et al. Rb regulates fate choice and lineage commitment in vivo. Nature 466, 1110–1114 (2010).
Article PubMed PubMed Central Google Scholar
- Scime, A. et al. Rb and p107 regulate preadipocyte differentiation into white versus brown fat through repression of PGC-1α. Cell Metab. 2, 283–295 (2005).
Article CAS PubMed Google Scholar
- Tsukiyama-Kohara, K. et al. Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1. Nat. Med. 7, 1128–1132 (2001).
Article CAS PubMed Google Scholar
- Leonardsson, G. et al. Nuclear receptor co-repressor RIP140 regulates fat accumulation. Proc. Natl Acad. Sci. USA 101, 8437–8442 (2004).
Article CAS PubMed PubMed Central Google Scholar
- Picard, F. et al. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell 111, 931–941 (2002).
Article CAS PubMed Google Scholar
- Bonet, M. L., Oliver, P. & Palou, A. Pharmacological and nutritional agents promoting browning of white adipose tissue. Biochim. Biophys. Acta 1831, 969–985 (2013).
Article CAS PubMed Google Scholar
- Cao, W. et al. p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol. Cell Biol. 24, 3057–3067 (2004).
Article CAS PubMed PubMed Central Google Scholar
- Martinez-deMena, R. & Obregón, M. J. Insulin increases the adrenergic stimulation of 5′ deiodinase activity and mRNA expression in rat brown adipocytes; role of MAPK and PI3K. J. Mol. Endocrinol. 34, 139–151 (2005).
Article CAS PubMed Google Scholar
- Muller, T. D. et al. p62 links β-adrenergic input to mitochondrial function and thermogenesis. J. Clin. Invest 123, 469–478 (2013).
Article CAS PubMed Google Scholar
- Ye, L. et al. Fat cells directly sense temperature to activate thermogenesis. Proc. Natl Acad. Sci. USA 110, 12480–12485 (2013).
Article PubMed PubMed Central Google Scholar
- Nedergaard, J. & Cannon, B. UCP1 mRNA does not produce heat. Biochim. Biophys. Acta 1831, 943–949 (2013).
Article CAS PubMed Google Scholar
- Puigserver, P. et al. A cold-inducible co-activator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).
Article CAS PubMed Google Scholar
- Hondares, E. et al. Thiazolidinediones and rexinoids induce peroxisome proliferator-activated receptor-co-activator (PGC)-1α gene transcription: an autoregulatory loop controls PGC-1α expression in adipocytes via peroxisome proliferator-activated receptor-γ co-activation. Endocrinology 147, 2829–2838 (2006).
Article CAS PubMed Google Scholar
- Hondares, E. et al. Peroxisome proliferator-activated receptor α (PPARα) induces PPARγ co-activator 1α (PGC-1α) gene expression and contributes to thermogenic activation of brown fat: involvement of PRDM16. J. Biol. Chem. 286, 43112–43122 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Wang, Y. X. et al. Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell 113, 159–170 (2003).
Article CAS PubMed Google Scholar
- Alvarez, 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. 270, 5666–5673 (1995).
Article CAS PubMed Google Scholar
- Mercader, J. et al. Remodeling of white adipose tissue after retinoic acid administration in mice. Endocrinology 147, 5325–5332 (2006).
Article CAS PubMed Google Scholar
- Kiefer, F. W. et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic programme in white adipose tissue. Nat. Med. 18, 918–925 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Pan, D., Fujimoto, M., Lopes, A. & Wang, Y. X. Twist-1 is a PPARδ-inducible, negative-feedback regulator of PGC-1α in brown fat metabolism. Cell 137, 73–86 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6, 38–54 (2007).
Article CAS PubMed PubMed Central Google Scholar
- Kajimura, S., Seale, P. & Spiegelman, B. M. Transcriptional control of brown fat development. Cell Metab. 11, 257–262 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Seale, P. et al. Prdm16 determines the thermogenic programme of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011).
Article 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).
Article CAS PubMed PubMed Central Google Scholar
- Ohno, H., Shinoda, K., Spiegelman, B. M. & Kajimura, S. PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 15, 395–404 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Trajkovski, M., Ahmed, K., Esau, C. C. & Stoffel, M. MyomiR-133 regulates brown fat differentiation through Prdm16. Nat. Cell Biol. 14, 1330–1335 (2012).
Article CAS PubMed Google Scholar
- Liu, W. et al. miR-133a regulates adipocyte browning in vivo. PLoS Genet. 9, e1003626 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Sun, L. et al. Mir193b-365 is essential for brown fat differentiation. Nat. Cell Biol. 13, 958–965 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Chen, Y. et al. miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit. Nat. Commun. 4, 1769 (2013).
Article CAS PubMed Google Scholar
- Mori, M., Nakagami, H., Rodriguez-Araujo, G., Nimura, K. & Kaneda, Y. Essential role for miR-196a in brown adipogenesis of white fat progenitor cells. PLoS Biol. 10, e1001314 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Galmozzi, A. et al. Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue. Diabetes 62, 732–742 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Villanueva, C. J. et al. Adipose subtype-selective recruitment of TLE3 or Prdm16 by PPARγ specifies lipid storage versus thermogenic gene programmes. Cell Metab. 17, 423–435 (2013).
Article 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).
Article CAS PubMed PubMed Central Google Scholar
- Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).
Article CAS PubMed Google Scholar
- Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Jager, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).
Article CAS PubMed PubMed Central Google Scholar
- Hawley, S. A. et al. Use of cells expressing γ subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11, 554–565 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Park, S. J. et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148, 421–433 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).
Article CAS PubMed Google Scholar
- Gaidhu, M. P. et al. Chronic AMP-kinase activation with AICAR reduces adiposity by remodeling adipocyte metabolism and increasing leptin sensitivity. J. Lipid Res. 52, 1702–1711 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Vila-Bedmar, R., Lorenzo, M. & Fernandez-Veledo, S. Adenosine 5′-monophosphate-activated protein kinase-mammalian target of rapamycin cross talk regulates brown adipocyte differentiation. Endocrinology 151, 980–992 (2010).
Article CAS PubMed Google Scholar
- Hawley, S. A. et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336, 918–922 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Haemmerle, G. et al. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1. Nat. Med. 17, 1076–1085 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Haemmerle, G. et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 312, 734–737 (2006).
Article CAS PubMed Google Scholar
- Ahmadian, M. et al. Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab. 13, 739–748 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Mottillo, E. P., Bloch, A. E., Leff, T. & Granneman, J. G. Lipolytic products activate peroxisome proliferator-activated receptor (PPAR) α and δ in brown adipocytes to match fatty acid oxidation with supply. J. Biol. Chem. 287, 25038–25048 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Nishino, N. et al. FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. J. Clin. Invest. 118, 2808–2821 (2008).
CAS PubMed PubMed Central Google Scholar
- Toh, S. Y. et al. Upregulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice. PLoS ONE 3, e2890 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Sawada, T. et al. Perilipin overexpression in white adipose tissue induces a brown fat-like phenotype. PLoS ONE 5, e14006 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Hotamisligil, G. S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900–917 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Singh, R. et al. Autophagy regulates adipose mass and differentiation in mice. J. Clin. Invest 119, 3329–3339 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Settembre, C. et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15, 647–658 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Heeren, J. & Munzberg, H. Novel aspects of brown adipose tissue biology. Endocrinol. Metab. Clin. North Am. 42, 89–107 (2013).
Article PubMed Google Scholar
- Nguyen, K. D. et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108 (2011).
Article 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).
Article CAS PubMed PubMed Central Google Scholar
- Madsen, L. et al. UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity. PLoS ONE 5, e11391 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Vegiopoulos, A. et al. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science 328, 1158–1161 (2010).
Article CAS PubMed Google Scholar
- Qian, S. W. et al. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc. Natl Acad. Sci. USA 110, E798–E807 (2013).
Article PubMed PubMed Central 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).
Article CAS PubMed PubMed Central Google Scholar
- Lodhi, I. J. et al. Inhibiting adipose tissue lipogenesis reprogrammes thermogenesis and PPARγ activation to decrease diet-induced obesity. Cell Metab. 16, 189–201 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Bartelt, A. et al. Effects of adipocyte lipoprotein lipase on de novo lipogenesis and white adipose tissue browning. Biochim. Biophys. Acta 1831, 934–942 (2013).
Article CAS 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).
Article CAS PubMed PubMed Central Google Scholar
- Hondares, E. et al. Hepatic FGF21 expression is induced at birth via PPARα in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab. 11, 206–212 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Kim, K. H. et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19, 83–92 (2013).
Article CAS PubMed 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).
Article 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).
Article CAS PubMed PubMed Central Google Scholar
- Tang, Q. Q., Otto, T. C. & Lane, M. D. Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc. Natl Acad. Sci. USA 101, 9607–9611 (2004).
Article CAS PubMed PubMed Central Google Scholar
- Bowers, R. R. & Lane, M. D. A role for bone morphogenetic protein-4 in adipocyte development. Cell Cycle 6, 385–389 (2007).
Article CAS PubMed Google Scholar
- Morrison, S. F., Madden, C. J. & Tupone, D. Central control of brown adipose tissue thermogenesis. Front. Endocrinol. 3, 00005 (2012).
Article CAS Google Scholar
- Di Marzo, V. & Matias, I. Endocannabinoid control of food intake and energy balance. Nat. Neurosci. 8, 585–589 (2005).
Article CAS PubMed Google Scholar
- Zeltser, L. M., Seeley, R. J. & Tschöp, M. H. Synaptic plasticity in neuronal circuits regulating energy balance. Nat. Neurosci. 15, 1336–1342 (2012).
Article CAS PubMed Google Scholar
- Yi, C. X. & Tschöp, M. H. Brain-gut-adipose-tissue communication pathways at a glance. Dis. Model. Mech. 5, 583–587 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Cao, L. et al. White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic–adipocyte axis. Cell Metab. 14, 324–338 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Paedersen, B. K. & Febbraio, M. A. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. 8, 457–465 (2012).
Article CAS Google Scholar
- Bordicchia, M. et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic programme in mouse and human adipocytes. J. Clin. Invest. 122, 1022–1036 (2012).
Article PubMed PubMed Central Google Scholar
- Mitschke, M. M. et al. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J. 27, 1621–1630 (2013).
Article CAS PubMed Google Scholar
- Sun, Z. Cardiovascular responses to cold exposure. Front. Biosci. (Elite Ed) 2, 495–503 (2010).
Article Google Scholar
- Handschin, C. & Spiegelman, B. M. The role of exercise and PGC1α in inflammation and chronic disease. Nature 454, 463–469 (2008).
Article 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).
Article CAS PubMed PubMed Central Google Scholar
- Zhang, C. et al. Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice. Diabetologia 55, 183–193 (2012).
Article CAS PubMed Google Scholar
- Shan, T., Liang, X., Bi, P. & Kuang, S. Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1α–Fndc5 pathway in muscle. FASEB J. 27, 1981–1989 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Ruas, J. L. et al. A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 151, 1319–1331 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Huh, J. Y. et al. FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise. Metabolism 61, 1725–1738 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Lecker, S. H. et al. Expression of the irisin precursor FNDC5 in skeletal muscle correlates with aerobic exercise performance in patients with heart failure. Circ. Heart Fail. 5, 812–818 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Moreno-Navarrete, J. M. et al. Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. J. Clin. Endocrinol. Metab. 98, E769–E778 (2013).
Article CAS PubMed Google Scholar
- Raschke S. et al. Evidence against a Beneficial Effect of Irisin in Humans. PLoS ONE 8, e73680 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Staiger, H. et al. Common genetic variation in the human FNDC5 locus, encoding the novel muscle-derived 'browning' factor irisin, determines insulin sensitivity. PLoS ONE 8, e61903 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Bartelt, A., Merkel, M. & Heeren, J. A new, powerful player in lipoprotein metabolism: brown adipose tissue. J. Mol. Med. (Berl.) 90, 887–893 (2012).
Article CAS Google Scholar
- Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).
Article CAS PubMed Google Scholar
- Stanford, K. I. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J. Clin. Invest. 123, 215–223 (2013).
Article CAS PubMed Google Scholar
- Liu, X. et al. Brown adipose tissue transplantation improves whole-body energy metabolism. Cell Res. 23, 851–854 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Kim, J. H., Bachmann, R. A. & Chen, J. Interleukin-6 and insulin resistance. Vitam. Horm. 80, 613–633 (2009).
Article CAS PubMed Google Scholar
- Guerra, C., Koza, R. A., Yamashita, H., Walsh, K. & Kozak, L. P. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J. Clin. Invest. 102, 412–420 (1998).
Article CAS PubMed PubMed Central Google Scholar
- Bachmanov, A. A., Reed, D. R., Tordoff, M. G., Price, R. A. & Beauchamp, G. K. Nutrient preference and diet-induced adiposity in C57BL/6ByJ and 129P3/J mice. Physiol. Behav. 72, 603–613 (2001).
Article CAS PubMed PubMed Central Google Scholar
- Tran, T. T., Yamamoto, Y., Gesta, S. & Kahn, C. R. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 7, 410–420 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Schulz, T. J. et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 495, 379–383 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Bal, N. C. et al. Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat. Med. 18, 1575–1579 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Chechi, K., Blanchard, P. G., Mathieu, P., Deshaies, Y. & Richard, D. Brown fat like gene expression in the epicardial fat depot correlates with circulating HDL-cholesterol and triglycerides in patients with coronary artery disease. Int. J. Cardiol. 167, 2264–2270 (2013).
Article PubMed Google Scholar
- Orava, J. et al. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab. 14, 272–279 (2011).
Article CAS PubMed Google Scholar
- Ouellet, V. et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J. Clin. Invest. 122, 545–552 (2012).
Article 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) http://dx.doi.org/10.1002/oby.20456.
- Nisoli, E. et al. Tumour necrosis factor α mediates apoptosis of brown adipocytes and defective brown adipocyte function in obesity. Proc. Natl Acad. Sci. USA 97, 8033–8038 (2000).
Article CAS PubMed PubMed Central Google Scholar
- Miranda, S., González-Rodriguez, A., Revuelta-Cervantes, J., Rondinone, C. M. & Valverde, A. M. Beneficial effects of PTP1B deficiency on brown adipocyte differentiation and protection against apoptosis induced by pro- and anti-inflammatory stimuli. Cell Signal. 22, 645–659 (2010).
Article CAS PubMed Google Scholar
- Bagchi, M. et al. Vascular endothelial growth factor is important for brown adipose tissue development and maintenance. FASEB J. 27, 3257–3271 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Xu, X. et al. Exercise ameliorates high-fat diet-induced metabolic and vascular dysfunction, and increases adipocyte progenitor cell population in brown adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300, R1115–R1125 (2011).
Article CAS PubMed PubMed Central Google Scholar
- Russell, A. P. et al. Brown adipocyte progenitor population is modified in obese and diabetic skeletal muscle. Int. J. Obes. (Lond.) 36, 155–158 (2012).
Article CAS Google Scholar
- Hu, H. H., Smith, D. L. Jr., Nayak, K. S., Goran, M. I. & Nagy, T. R. Identification of brown adipose tissue in mice with fat-water IDEAL-MRI. J. Magn. Reson. Imaging 31, 1195–1202 (2010).
Article PubMed PubMed Central Google Scholar
- Chen, Y. I. et al. Anatomical and functional assessment of brown adipose tissue by magnetic resonance imaging. Obesity (Silver Spring) 20, 1519–1526 (2012).
Article CAS Google Scholar
- Iris Chen, Y. C. et al. Measurement of human brown adipose tissue volume and activity using anatomic MR imaging and functional MR imaging. J. Nucl. Med. 54, 1584–1587 (2013).
Article CAS Google Scholar
- Vliegenthart, R. et al. Dual-energy CT of the heart. AJR Am. J. Roentgenol. 199 (Suppl. 5), S54–S63 (2012).
Article PubMed Google Scholar
- Bruns, O. T. et al. Real-time magnetic resonance imaging and quantification of lipoprotein metabolism in vivo using nanocrystals. Nat. Nanotechnol. 4, 193–201 (2009).
Article CAS PubMed Google Scholar
- Heeren, J. & Bruns, O. Nanocrystals, a new tool to study lipoprotein metabolism and atherosclerosis. Curr. Pharm. Biotechnol. 13, 365–372 (2012).
Article CAS PubMed Google Scholar