The brain and brown fat

References

• Lowell BB, Spiegelman BM. Towards a molecular understanding of adaptive thermogenesis. Nature. 2000;404:652–60.
   PubMed Web of Science ®Google Scholar
• Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84:277–359.
   PubMed Web of Science ®Google Scholar
• van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360:1500–8.
   PubMed Web of Science ®Google Scholar
• Tran TT, Kahn CR. Transplantation of adipose tissue and stem cells: role in metabolism and disease. Nat Rev Endocrinol. 2010;6:195–213.
   PubMed Web of Science ®Google Scholar
• Whittle AJ, López M, Vidal-Puig A. Using brown adipose tissue to treat obesity - the central issue. Trends Mol Med. 2011;17:405–11.
   PubMed Web of Science ®Google Scholar
• Whittle A, Relat-Pardo J, Vidal-Puig A. Pharmacological strategies for targeting BAT thermogenesis. Trends Pharmacol Sci. 2013;34: 347–55.
   Google Scholar
• Carobbio S, Rosen B, Vidal-Puig A. Adipogenesis: new insights into brown adipose tissue differentiation. J Mol Endocrinol. 2013;51: T75–85.
   PubMed Web of Science ®Google Scholar
• Villarroya F, Vidal-Puig A. Beyond the sympathetic tone: the new brown fat activators. Cell Metab. 2013;17:638–43.
   PubMed Web of Science ®Google Scholar
• Villarroya J, Cereijo R, Villarroya F. An endocrine role for brown adipose tissue?Am J Physiol Endocrinol Metab. 2013;305:E567–72.
   PubMed Web of Science ®Google Scholar
• Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: is beige the new brown?Genes Dev. 2013;27:234–50.
   PubMed Web of Science ®Google Scholar
• Granneman JG. Norepinephrine infusions increase adenylate cyclase responsiveness in brown adipose tissue. J Pharmacol Exp Ther. 1988;245:1075–80.
   PubMed Web of Science ®Google Scholar
• Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, 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. 2009;23:3113–20.
   PubMed Web of Science ®Google Scholar
• Goossens GH. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav. 2008;94:206–18.
   PubMed Web of Science ®Google Scholar
• Timmons JA, Wennmalm K, Larsson O, Walden TB, Lassmann T, Petrovic N, et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc Natl Acad Sci U S A. 2007;104:4401–6.
   PubMed Web of Science ®Google Scholar
• Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454:961–7.
   PubMed Web of Science ®Google Scholar
• Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 2008;454: 1000–4.
   PubMed Web of Science ®Google Scholar
• Sharp LZ, Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L, et al. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One. 2012;7:e49452.
   PubMed Web of Science ®Google Scholar
• Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150:366–76.
   PubMed Web of Science ®Google Scholar
• Jespersen NZ, Larsen TJ, Peijs L, Daugaard S, Homoe P, Loft A, et al. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab. 2013;17:798–805.
   PubMed Web of Science ®Google Scholar
• Lee P, Werner CD, Kebebew E, Celi FS. Functional thermogenic beige adipogenesis is inducible in human neck fat. Int J Obes (Lond). 2014;38:170–6.
   PubMed Web of Science ®Google Scholar
• Lidell ME, Betz MJ, Dahlqvist LO, Heglind M, Elander L, Slawik M, et al. Evidence for two types of brown adipose tissue in humans. Nat Med. 2013;19:631–4.
   PubMed Web of Science ®Google Scholar
• Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) 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. 2010;285:7153–64.
   PubMed Web of Science ®Google Scholar
• Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV, Cannon B, Nedergaard J. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep. 2013;5:1196–203.
   PubMed Web of Science ®Google Scholar
• Walden TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J. Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. Am J Physiol Endocrinol Metab. 2012;302: E19–31.
   PubMed Web of Science ®Google Scholar
• Nedergaard J, Cannon B. UCP1 mRNA does not produce heat. Biochim Biophys Acta. 2013;1831:943–9.
   PubMed Web of Science ®Google Scholar
• Keipert S, Jastroch M. Brite/beige fat and UCP1 - is it thermogenesis? Biochim Biophys Acta. 2014 Feb 14. [Epub ahead of print].
   Google Scholar
• Nedergaard J, Lindberg O. The brown fat cell. Int Rev Cytol. 1982;74:187–286.
   Google Scholar
• Nicholls DG. Hamster brown-adipose-tissue mitochondria. The control of respiration and the proton electrochemical potential gradient by possible physiological effectors of the proton conductance of the inner membrane. Eur J Biochem. 1974;49:573–83.
   Google Scholar
• Heaton GM, Wagenvoord RJ, Kemp A Jr, Nicholls DG. Brown-adipose-tissue mitochondria: photoaffinity labelling of the regulatory site of energy dissipation. Eur J Biochem. 1978;82:515–21.
   PubMedGoogle Scholar
• Garlid KD, Jaburek M, Jezek P, Varecha M. How do uncoupling proteins uncouple?Biochim Biophys Acta. 2000;1459:383–9.
   PubMed Web of Science ®Google Scholar
• Jaburek M, Varecha M, Jezek P, Garlid KD. Alkylsulfonates as probes of uncoupling protein transport mechanism. Ion pair transport demonstrates that direct H(+) translocation by UCP1 is not necessary for uncoupling. J Biol Chem. 2001;276:31897–905.
   Google Scholar
• van Marken Lichtenbelt WD, Schrauwen P. Implications of nonshivering thermogenesis for energy balance regulation in humans. Am J Physiol Regul Integr Comp Physiol. 2011;301:R285–96.
   PubMed Web of Science ®Google Scholar
• Cypess AM, Kahn CR. Brown fat as a therapy for obesity and diabetes. Curr Opin Endocrinol Diabetes Obes. 2010;17:143–9.
   PubMed Web of Science ®Google Scholar
• Cao W, Medvedev AV, Daniel KW, Collins S. beta-Adrenergic activation of p38 MAP kinase in adipocytes: cAMP induction of the uncoupling protein 1 (UCP1) gene requires p38 MAP kinase. J Biol Chem. 2001;276:27077–82.
   PubMed Web of Science ®Google Scholar
• Holm C, Fredrikson G, Cannon B, Belfrage P. Hormone-sensitive lipase in brown adipose tissue: identification and effect of cold exposure. Biosci Rep. 1987;7:897–904.
   PubMed Web of Science ®Google Scholar
• Shih MF, Taberner PV. Selective activation of brown adipocyte hormone-sensitive lipase and cAMP production in the mouse by beta 3-adrenoceptor agonists. Biochem Pharmacol. 1995;50: 601–8.
   Google Scholar
• Clifford GM, Londos C, Kraemer FB, Vernon RG, Yeaman SJ. Translocation of hormone-sensitive lipase and perilipin upon lipolytic stimulation of rat adipocytes. J Biol Chem. 2000;275:5011–15.
   PubMed Web of Science ®Google Scholar
• Morimoto C, Kameda K, Tsujita T, Okuda H. Relationships between lipolysis induced by various lipolytic agents and hormone-sensitive lipase in rat fat cells. J Lipid Res. 2001;42:120–7.
   PubMed Web of Science ®Google Scholar
• Bukowiecki LJ, Geloen A, Collet AJ. Proliferation and differentiation of brown adipocytes from interstitial cells during cold acclimation. Am J Physiol. 1986;250:C880–7.
   PubMed Web of Science ®Google Scholar
• Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17:200–5.
   PubMed Web of Science ®Google Scholar
• Guerra C, Navarro P, Valverde AM, Arribas M, Bruning J, Kozak LP, et al. Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. J Clin Invest. 2001; 108:1205–13.
   PubMed Web of Science ®Google Scholar
• Gunawardana SC, Piston DW. Reversal of type 1 diabetes in mice by brown adipose tissue transplant. Diabetes. 2012;61:674–82.
   PubMed Web of Science ®Google Scholar
• Meyer CW, Willershauser M, Jastroch M, Rourke BC, Fromme T, Oelkrug R, et al. Adaptive thermogenesis and thermal conductance in wild-type and UCP1-KO mice. Am J Physiol Regul Integr Comp Physiol. 2010;299:R1396–406.
   PubMed Web of Science ®Google Scholar
• Mercer SW, Trayhurn P. Effect of high fat diets on energy balance and thermogenesis in brown adipose tissue of lean and genetically obese ob/ob mice. J Nutr. 1987;117:2147–53.
   PubMed Web of Science ®Google Scholar
• Dong M, Yang X, Lim S, Cao Z, Honek J, Lu H, et al. Cold exposure promotes atherosclerotic plaque growth and instability via UCP1- dependent lipolysis. Cell Metab. 2013;18:118–29.
   PubMed Web of Science ®Google Scholar
• Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007;293:E444–52.
   PubMed Web of Science ®Google Scholar
• Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360:1509–17.
   PubMed Web of Science ®Google Scholar
• Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009;360:1518–25.
   PubMed Web of Science ®Google Scholar
• Ishibashi J, Seale P. Medicine. Beige can be slimming. Science. 2010;328:1113–14.
   PubMed Web of Science ®Google Scholar
• Aune UL, Ruiz L, Kajimura S. Isolation and differentiation of stromal vascular cells to beige/brite cells. J Vis Exp. 2013 Mar 28. doi: 10.3791/50191.
   PubMedGoogle Scholar
• Nakamura Y, Sato T, Shiimura Y, Miura Y, Kojima M. FABP3 and brown adipocyte-characteristic mitochondrial fatty acid oxidation enzymes are induced in beige cells in a different pathway from UCP1. Biochem Biophys Res Commun. 2013;441:42–6.
   PubMed Web of Science ®Google Scholar
• Lee YK, Cowan CA. White to brite adipocyte transition and back again. Nat Cell Biol. 2013;15:568–9.
   Google Scholar
• Whittle A, Vidal-Puig A. When BAT is lacking, WAT steps up. Cell Res. 2013;23:868–9.
   Google Scholar
• Spiegelman BM, Puigserver P, Wu Z. Regulation of adipogenesis and energy balance by PPARgamma and PGC-1. Int J Obes Relat Metab Disord. 2000;24(Suppl 4):S8–10.
   Google Scholar
• Tiraby C, Tavernier G, Lefort C, Larrouy D, Bouillaud F, Ricquier D, et al. Acquirement of brown fat cell features by human white adipocytes. J Biol Chem. 2003;278:33370–6.
   PubMed Web of Science ®Google Scholar
• Uldry M, Yang W, St-Pierre J, Lin J, Seale P, Spiegelman BM. Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab. 2006;3:333–41.
   PubMed Web of Science ®Google Scholar
• Ohno H, Shinoda K, Spiegelman BM, Kajimura S. PPARgamma agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 2012;15:395–404.
   PubMed Web of Science ®Google Scholar
• Qiang L, Wang L, Kon N, Zhao W, Lee S, Zhang Y, et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Ppargamma. Cell. 2012;150:620–32.
   PubMed Web of Science ®Google Scholar
• Seale P, Kajimura S, Spiegelman BM. Transcriptional control of brown adipocyte development and physiological function—of mice and men. Genes Dev. 2009;23:788–97.
   PubMed Web of Science ®Google Scholar
• Seale P. Transcriptional control of brown adipocyte development and thermogenesis. Int J Obes (Lond). 2010;34(Suppl 1):S17–22.
   Google Scholar
• Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994;8:1224–34.
   PubMed Web of Science ®Google Scholar
• Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994;79:1147–56.
   PubMed Web of Science ®Google Scholar
• Medina-Gomez G, Virtue S, Lelliott C, Boiani R, Campbell M, Christodoulides C, et al. The link between nutritional status and insulin sensitivity is dependent on the adipocyte-specific peroxisome proliferator-activated receptor-gamma2 isoform. Diabetes. 2005; 54:1706–16.
   PubMed Web of Science ®Google Scholar
• Medina-Gomez G, Gray S, Vidal-Puig A. Adipogenesis and lipotoxicity: role of peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgammacoactivator-1 (PGC1). Public Health Nutr. 2007;10:1132–7.
   PubMed Web of Science ®Google Scholar
• Wang F, Mullican SE, DiSpirito JR, Peed LC, Lazar MA. Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARgamma. Proc Natl Acad Sci U S A. 2013;110: 18656–61.
   PubMed Web of Science ®Google Scholar
• Kajimura S, Seale P, Tomaru T, Erdjument-Bromage H, Cooper MP, Ruas JL, et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev. 2008;22:1397–409.
   PubMed Web of Science ®Google Scholar
• Walden TB, Petrovic N, Nedergaard J. PPARalpha does not suppress muscle-associated gene expression in brown adipocytes but does influence expression of factors that fingerprint the brown adipocyte. Biochem Biophys Res Commun. 2010;397:146–51.
   PubMed Web of Science ®Google Scholar
• Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998;92:829–39.
   PubMed Web of Science ®Google Scholar
• Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999;98: 115–24.
   PubMed Web of Science ®Google Scholar
• Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 2008;77:289–312.
   PubMed Web of Science ®Google Scholar
• Fruhbeck G, Sesma P, Burrell MA. PRDM16: the interconvertible adipo-myocyte switch. Trends Cell Biol. 2009;19:141–6.
   PubMedGoogle Scholar
• Fruhbeck G, Becerril S, Sainz N, Garrastachu P, Garcia-Velloso MJ. BAT: a new target for human obesity?Trends Pharmacol Sci. 2009;30:387–96.
   Google Scholar
• Park KW, Halperin DS, Tontonoz P. Before they were fat: adipocyte progenitors. Cell Metab. 2008;8:454–7.
   PubMed Web of Science ®Google Scholar
• Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest. 2011;121:96–105.
   PubMed Web of Science ®Google Scholar
• Christian M, White R, Parker MG. Metabolic regulation by the nuclear receptor corepressor RIP140. Trends Endocrinol Metab. 2006;17: 243–50.
   PubMed Web of Science ®Google Scholar
• Leonardsson G, Steel JH, Christian M, Pocock V, Milligan S, Bell J, et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc Natl Acad Sci U S A. 2004;101:8437–42.
   PubMed Web of Science ®Google Scholar
• Christian M, Kiskinis E, Debevec D, Leonardsson G, White R, Parker MG. RIP140-targeted repression of gene expression in adipocytes. Mol Cell Biol. 2005;25:9383–91.
   PubMed Web of Science ®Google Scholar
• Powelka AM, Seth A, Virbasius JV, Kiskinis E, Nicoloro SM, Guilherme A, et al. Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. J Clin Invest. 2006;116:125–36.
   PubMed Web of Science ®Google Scholar
• Seth A, Steel JH, Nichol D, Pocock V, Kumaran MK, Fritah A, et al. The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle. Cell Metab. 2007;6:236–45.
   PubMed Web of Science ®Google Scholar
• Wang L, Li Y, Hu P, Teng CT. PGC-1alpha induces dynamic protein interactions on the ERRalpha gene multi-hormone response element nucleosome in kidney cells. Biochem J. 2008;416:407–19.
   Google Scholar
• Hallberg M, Morganstein DL, Kiskinis E, Shah K, Kralli A, Dilworth SM, et al. A functional interaction between RIP140 and PGC-1alpha regulates the expression of the lipid droplet protein CIDEA. Mol Cell Biol. 2008;28:6785–95.
   PubMed Web of Science ®Google Scholar
• Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481:463–8.
   PubMed Web of Science ®Google Scholar
• Goto M, Terada S, Kato M, Katoh M, Yokozeki T, Tabata I, et al. cDNA Cloning and mRNA analysis of PGC-1 in epitrochlearis muscle in swimming-exercised rats. Biochem Biophys Res Commun. 2000; 274:350–4.
   PubMedGoogle Scholar
• Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, et al. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J. 2002;16:1879–86.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, et al. Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes. 2014;63:514–25.
   PubMed Web of Science ®Google Scholar
• Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 2014;19:302–9.
   PubMed Web of Science ®Google Scholar
• Raschke S, Elsen M, Gassenhuber H, Sommerfeld M, Schwahn U, Brockmann B, et al. Evidence against a beneficial effect of irisin in humans. PLoS One. 2013;8:e73680.
   PubMed Web of Science ®Google Scholar
• Pekkala S, Wiklund PK, Hulmi JJ, Ahtiainen JP, Horttanainen M, Pollanen E, et al. Are skeletal muscle FNDC5 gene expression and irisin release regulated by exercise and related to health?J Physiol. 2013;591:5393–400.
   PubMed Web of Science ®Google Scholar
• Roca-Rivada A, Castelao C, Senin LL, Landrove MO, Baltar J, Belen CA, et al. FNDC5/irisin is not only a myokine but also an adipokine. PLoS One. 2013;8:e60563.
   PubMed Web of Science ®Google Scholar
• Novelle MG, Contreras C, Romero-Pico A, López M, Diéguez C. Irisin, two years later. Int J Endocrinol. 2013;2013:746281.
   Google Scholar
• McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002;416:52–8.
   PubMed Web of Science ®Google Scholar
• Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, et al. A TRP channel that senses cold stimuli and menthol. Cell. 2002;108:705–15.
   PubMed Web of Science ®Google Scholar
• Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature. 2007;448:204–8.
   PubMed Web of Science ®Google Scholar
• Colburn RW, Lubin ML, Stone DJ Jr, Wang Y, Lawrence D, D’Andrea MR, et al. Attenuated cold sensitivity in TRPM8 null mice. Neuron. 2007;54:379–86.
   PubMed Web of Science ®Google Scholar
• Dhaka A, Murray AN, Mathur J, Earley TJ, Petrus MJ, Patapoutian A. TRPM8 is required for cold sensation in mice. Neuron. 2007;54:371–8.
   PubMed Web of Science ®Google Scholar
• Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell. 2003;112:819–29.
   PubMed Web of Science ®Google Scholar
• Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, et al. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron. 2004;41:849–57.
   PubMed Web of Science ®Google Scholar
• Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature. 2004;427:260–5.
   PubMed Web of Science ®Google Scholar
• Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816–24.
   PubMed Web of Science ®Google Scholar
• Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 1998;21:531–43.
   PubMed Web of Science ®Google Scholar
• Guler AD, Lee H, Iida T, Shimizu I, Tominaga M, Caterina M. Heat-evoked activation of the ion channel, TRPV4. J Neurosci. 2002;22:6408–14.
   PubMed Web of Science ®Google Scholar
• Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, et al. A heat-sensitive TRP channel expressed in keratinocytes. Science. 2002;296:2046–9.
   PubMed Web of Science ®Google Scholar
• Smith GD, Gunthorpe MJ, Kelsell RE, Hayes PD, Reilly P, Facer P, et al. TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature. 2002;418:186–90.
   PubMed Web of Science ®Google Scholar
• Watanabe H, Davis JB, Smart D, Jerman JC, Smith GD, Hayes P, et al. Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. J Biol Chem. 2002;277:13569–77.
   PubMed Web of Science ®Google Scholar
• Xu H, Ramsey IS, Kotecha SA, Moran MM, Chong JA, Lawson D, et al. TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature. 2002;418:181–6.
   PubMed Web of Science ®Google Scholar
• Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, et al. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell. 2000;103: 525–35.
   PubMed Web of Science ®Google Scholar
• Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD. OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol. 2000;2:695–702.
   PubMed Web of Science ®Google Scholar
• Ye L, Kleiner S, Wu J, Sah R, Gupta RK, Banks AS, et al. TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell. 2012;151:96–110.
   PubMed Web of Science ®Google Scholar
• Woudenberg-Vrenken TE, Bindels RJ, Hoenderop JG. The role of transient receptor potential channels in kidney disease. Nat Rev Nephrol. 2009;5:441–9.
   Google Scholar
• Sinke AP, Deen PM. The physiological implication of novel proteins in systemic osmoregulation. FASEB J. 2011;25:3279–89.
   PubMed Web of Science ®Google Scholar
• Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessi-Fulgheri P, Zhang C, et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest. 2012;122:1022–36.
   PubMed Web of Science ®Google Scholar
• Schwarz EJ, Reginato MJ, Shao D, Krakow SL, Lazar MA. Retinoic acid blocks adipogenesis by inhibiting C/EBPbeta-mediated transcription. Mol Cell Biol. 1997;17:1552–61.
   PubMed Web of Science ®Google Scholar
• Ziouzenkova O, Plutzky J. Retinoid metabolism and nuclear receptor responses: new insights into coordinated regulation of the PPAR-RXR complex. FEBS Lett. 2008;582:32–8.
   PubMed Web of Science ®Google Scholar
• Kane MA, Folias AE, Pingitore A, Perri M, Krois CR, Ryu JY, et al. CrbpI modulates glucose homeostasis and pancreas 9-cis-retinoic acid concentrations. Mol Cell Biol. 2011;31:3277–85.
   PubMedGoogle Scholar
• Mercader J, Ribot J, Murano I, Felipe F, Cinti S, Bonet ML, et al. Remodeling of white adipose tissue after retinoic acid administration in mice. Endocrinology. 2006;147:5325–32.
   PubMed Web of Science ®Google Scholar
• Kiefer FW, Vernochet C, O’Brien P, Spoerl S, Brown JD, Nallamshetty S, et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat Med. 2012;18: 918–25.
   PubMed Web of Science ®Google Scholar
• Vegiopoulos A, Muller-Decker K, Strzoda D, Schmitt I, Chichelnitskiy E, Ostertag A, et al. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science. 2010;328:1158–61.
   PubMedGoogle Scholar
• Madsen L, Pedersen LM, Lillefosse HH, Fjaere E, Bronstad I, Hao Q, et al. UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity. PLoS One. 2010;5:e11391.
   PubMed Web of Science ®Google Scholar
• Virtue S, Feldmann H, Christian M, Tan CY, Masoodi M, Dale M, et al. A new role for lipocalin prostaglandin d synthase in the regulation of brown adipose tissue substrate utilization. Diabetes. 2012;61: 3139–47.
   Google Scholar
• Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev. 2008;29:898–938.
   PubMed Web of Science ®Google Scholar
• Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010;31:139–70.
   PubMed Web of Science ®Google Scholar
• Brent GA. Mechanisms of thyroid hormone action. J Clin Invest. 2012;122:3035–43.
   PubMed Web of Science ®Google Scholar
• Warner A, Mittag J. Thyroid hormone and the central control of homeostasis. J Mol Endocrinol. 2012;49:R29–35.
   PubMed Web of Science ®Google Scholar
• López M, Alvarez CV, Nogueiras R, Diéguez C. Energy balance regulation by thyroid hormones at central level. Trends Mol Med. 2013;19:418–27.
   PubMed Web of Science ®Google Scholar
• López M, Seoane L, Señarís RM, Diéguez C. Prepro-orexin mRNA levels in the rat hypothalamus, and orexin receptors mRNA levels in the rat hypothalamus and adrenal gland are not influenced by the thyroid status. Neurosci Lett. 2001;300:171–5.
   Google Scholar
• López M, Seoane L, Tovar S, Señarís RM, Diéguez C. Thyroid status regulates CART but not AgRP mRNA levels in the rat hypothalamus. Neuroreport. 2002;13:1775–9.
   Google Scholar
• López M, Varela L, Vázquez MJ, Rodriguez-Cuenca S, González CR, Velagapudi VR, et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med. 2010;16:1001–8.
   PubMed Web of Science ®Google Scholar
• González CR, Martínez de Morentin PB, Martínez-Sanchez N, Gomez-Diaz C, Lage R, Varela L, et al. Hyperthyroidism differentially regulates neuropeptide S system in the rat brain. Brain Res. 2012; 1450:40–8.
   Google Scholar
• Varela L, Martínez-Sanchez N, Gallego R, Vázquez MJ, Roa J, Gandara M, et al. Hypothalamic mTOR pathway mediates thyroid hormone-induced hyperphagia in hyperthyroidism. J Pathol. 2012; 227:209–22.
   PubMedGoogle Scholar
• Silva JE. Thermogenic mechanisms and their hormonal regulation. Physiol Rev. 2006;86:435–64.
   PubMed Web of Science ®Google Scholar
• Dicker A, Raasmaja A, Cannon B, Nedergaard J. Increased alpha 1-adrenoceptor density in brown adipose tissue indicates recruitment drive in hypothyroid rats. Am J Physiol. 1992;263:E654–62.
   PubMed Web of Science ®Google Scholar
• Gordon CJ. Behavioral and autonomic thermoregulation in the rat following propylthiouracil-induced hypothyroidism. Pharmacol Biochem Behav. 1997;58:231–6.
   PubMedGoogle Scholar
• Kim B. Thyroid hormone as a determinant of energy expenditure and the basal metabolic rate. Thyroid. 2008;18:141–4.
   PubMedGoogle Scholar
• Sainsbury A, Zhang L. Role of the hypothalamus in the neuroendocrine regulation of body weight and composition during energy deficit. Obes Rev. 2012;13:234–57.
   PubMedGoogle Scholar
• Bianco AC, Sheng XY, Silva JE. Triiodothyronine amplifies norepinephrine stimulation of uncoupling protein gene transcription by a mechanism not requiring protein synthesis. J Biol Chem. 1988;263:18168–75.
   PubMed Web of Science ®Google Scholar
• Martínez de Mena R, Scanlan TS, Obregon MJ. The T3 receptor beta1 isoform regulates UCP1 and D2 deiodinase in rat brown adipocytes. Endocrinology. 2010;151:5074–83.
   Google Scholar
• Ribeiro MO, Bianco SD, Kaneshige M, Schultz JJ, Cheng SY, Bianco AC, et al. Expression of uncoupling protein 1 in mouse brown adipose tissue is thyroid hormone receptor-beta isoform specific and required for adaptive thermogenesis. Endocrinology. 2010;151: 432–40.
   Google Scholar
• Wikstrom L, Johansson C, Salto C, Barlow C, Campos BA, Baas F, et al. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J. 1998;17: 455–61.
   PubMed Web of Science ®Google Scholar
• Golozoubova V, Gullberg H, Matthias A, Cannon B, Vennstrom B, Nedergaard J. Depressed thermogenesis but competent brown adipose tissue recruitment in mice devoid of all hormone-binding thyroid hormone receptors. Mol Endocrinol. 2004;18:384–401.
   PubMedGoogle Scholar
• Marrif H, Schifman A, Stepanyan Z, Gillis MA, Calderone A, Weiss RE, et al. Temperature homeostasis in transgenic mice lacking thyroid hormone receptor-alpha gene products. Endocrinology. 2005;146: 2872–84.
   Google Scholar
• Sjogren M, Alkemade A, Mittag J, Nordstrom K, Katz A, Rozell B, et al. Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor alpha1. EMBO J. 2007;26: 4535–45.
   Google Scholar
• Ramadan W, Marsili A, Larsen PR, Zavacki AM, Silva JE. Type-2 iodothyronine 5'deiodinase (D2) in skeletal muscle of C57Bl/6 mice. II. Evidence for a role of D2 in the hypermetabolism of thyroid hormone receptor alpha-deficient mice. Endocrinology. 2011;152: 3093–102.
   Google Scholar
• Bianco AC, Silva JE. Optimal response of key enzymes and uncoupling protein to cold in BAT depends on local T3 generation. Am J Physiol. 1987;253:E255–63.
   PubMed Web of Science ®Google Scholar
• Bianco AC, Silva JE. Intracellular conversion of thyroxine to triiodothyronine is required for the optimal thermogenic function of brown adipose tissue. J Clin Invest. 1987;79:295–300.
   PubMed Web of Science ®Google Scholar
• Bianco AC, Silva JE. Nuclear 3,5,3’-triiodothyronine (T3) in brown adipose tissue: receptor occupancy and sources of T3 as determined by in vivo techniques. Endocrinology. 1987;120:55–62.
   PubMed Web of Science ®Google Scholar
• Bianco AC, Silva JE. Cold exposure rapidly induces virtual saturation of brown adipose tissue nuclear T3 receptors. Am J Physiol. 1988;255:E496–503.
   Google Scholar
• de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim SW, Harney JW, et al. The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest. 2001;108:1379–85.
   PubMed Web of Science ®Google Scholar
• Christoffolete MA, Linardi CC, de Jesus L, Ebina KN, Carvalho SD, Ribeiro MO, et al. Mice with targeted disruption of the Dio2 gene have cold-induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis. Diabetes. 2004;53:577–84.
   PubMed Web of Science ®Google Scholar
• Castillo M, Hall JA, Correa-Medina M, Ueta C, Kang HW, Cohen DE, et al. Disruption of thyroid hormone activation in type 2 deiodinase knockout mice causes obesity with glucose intolerance and liver steatosis only at thermoneutrality. Diabetes. 2011; 60:1082–9.
   PubMed Web of Science ®Google Scholar
• Skarulis MC, Celi FS, Mueller E, Zemskova M, Malek R, Hugendubler L, et al. Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance. J Clin Endocrinol Metab. 2010;95:256–62.
   PubMed Web of Science ®Google Scholar
• Casanueva FF, Diéguez C. Neuroendocrine regulation and actions of leptin. Front Neuroendocrinol. 1999;20:317–63.
   PubMed Web of Science ®Google Scholar
• Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000;62:413–37.
   PubMed Web of Science ®Google Scholar
• Friedman JM. The function of leptin in nutrition, weight, and physiology. Nutr Rev. 2002;60:S1–14.
   Web of Science ®Google Scholar
• Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell. 2004;116:337–50.
   PubMed Web of Science ®Google Scholar
• Friedman JM. Leptin at 14 y of age: an ongoing story. Am J Clin Nutr. 2009;89:973S–9S.
   PubMed Web of Science ®Google Scholar
• Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest. 1997;100:270–8.
   PubMed Web of Science ®Google Scholar
• Ueno N, Oh-ishi S, Segawa M, Nishida M, Fukuwatari Y, Kizaki T, et al. Effect of age on brown adipose tissue activity in the obese (ob/ob) mouse. Mech Ageing Dev. 1998;100:67–76.
   Google Scholar
• Commins SP, Watson PM, Levin N, Beiler RJ, Gettys TW. Central leptin regulates the UCP1 and ob genes in brown and white adipose tissue via different beta-adrenoceptor subtypes. J Biol Chem. 2000; 275:33059–67.
   Google Scholar
• Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001; 411:480–4.
   PubMed Web of Science ®Google Scholar
• Storlien LH, James DE, Burleigh KM, Chisholm DJ, Kraegen EW. Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats. Am J Physiol. 1986;251: E576–83.
   PubMed Web of Science ®Google Scholar
• Smith DM, Bloom SR, Sugden MC, Holness MJ. Glucose transporter expression and glucose utilization in skeletal muscle and brown adipose tissue during starvation and re-feeding. Biochem J. 1992; 282(Pt 1):231–5.
   Google Scholar
• Sugden MC, Holness MJ. Physiological modulation of the uptake and fate of glucose in brown adipose tissue. Biochem J. 1993; 295(Pt 1):171–6.
   Google Scholar
• Vallerand AL, Lupien J, Bukowiecki LJ. Interactions of cold exposure and starvation on glucose tolerance and insulin response. Am J Physiol. 1983;245:E575–81.
   PubMed Web of Science ®Google Scholar
• Rahmouni K, Morgan DA, Morgan GM, Liu X, Sigmund CD, Mark AL, et al. Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin. J Clin Invest. 2004;114:652–8.
   PubMed Web of Science ®Google Scholar
• Orava J, Nuutila P, Lidell ME, Oikonen V, Noponen T, Viljanen T, et al. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab. 2011;14:272–9.
   PubMed Web of Science ®Google Scholar
• Ortega-Molina A, Efeyan A, López-Guadamillas E, Munoz-Martin M, Gomez-López G, Canamero M, et al. Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell Metab. 2012;15:382–94.
   PubMed Web of Science ®Google Scholar
• Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem. 1996;271:10697–703.
   PubMed Web of Science ®Google Scholar
• Tsao TS, Lodish HF, Fruebis J. ACRP30, a new hormone controlling fat and glucose metabolism. Eur J Pharmacol. 2002;440:213–21.
   PubMed Web of Science ®Google Scholar
• Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7:947–53.
   PubMed Web of Science ®Google Scholar
• Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab. 2002;13:84–9.
   PubMed Web of Science ®Google Scholar
• Caminos JE, Nogueiras R, Gallego R, Bravo S, Tovar S, Garcia-Caballero T, et al. Expression and regulation of adiponectin and receptor in human and rat placenta. J Clin Endocrinol Metab. 2005;90:4276–86.
   PubMed Web of Science ®Google Scholar
• Pineiro R, Iglesias MJ, Gallego R, Raghay K, Eiras S, Rubio J, et al. Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Lett. 2005;579:5163–9.
   PubMed Web of Science ®Google Scholar
• Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941–6.
   PubMed Web of Science ®Google Scholar
• Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 2007;6:55–68.
   PubMed Web of Science ®Google Scholar
• Guillod-Maximin E, Roy AF, Vacher CM, Aubourg A, Bailleux V, Lorsignol A, et al. Adiponectin receptors are expressed in hypothalamus and colocalized with proopiomelanocortin and neuropeptide Y in rodent arcuate neurons. J Endocrinol. 2009;200:93–105.
   PubMedGoogle Scholar
• Wen JP, Liu CE, Hu YT, Chen G, Lin LX. Globular adiponectin regulates energy homeostasis through AMP-activated protein kinase-acetyl-CoA carboxylase (AMPK/ACC) pathway in the hypothalamus. Mol Cell Biochem. 2010;344:109–15.
   Google Scholar
• Qiao L, Kinney B, Schaack J, Shao J. Adiponectin inhibits lipolysis in mouse adipocytes. Diabetes. 2011;60:1519–27.
   PubMed Web of Science ®Google Scholar
• Kajimura D, Lee HW, Riley KJ, Arteaga-Solis E, Ferron M, Zhou B, et al. Adiponectin regulates bone mass via opposite central and peripheral mechanisms through FoxO1. Cell Metab. 2013;17:901–15.
   PubMed Web of Science ®Google Scholar
• Qiao L, Yoo HS, Bosco C, Lee B, Feng GS, Schaack J, et al. Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice. Diabetologia. 2014;57:1027–36.
   PubMed Web of Science ®Google Scholar
• Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409:307–12.
   PubMed Web of Science ®Google Scholar
• Nogueiras R, Novelle MG, Vázquez MJ, López M, Diéguez C. Resistin: regulation of food intake, glucose homeostasis and lipid metabolism. Endocr Dev. 2010;17:175–84.
   Google Scholar
• Kosari S, Rathner JA, Badoer E. Central resistin enhances renal sympathetic nerve activity via phosphatidylinositol 3-kinase but reduces the activity to brown adipose tissue via extracellular signal-regulated kinase. J Neuroendocrinol. 2012;24:1432–9.
   Google Scholar
• Kosari S, Camera DM, Hawley JA, Stebbing M, Badoer E. ERK1/2 in the brain mediates the effects of central resistin on reducing thermogenesis in brown adipose tissue. Int J Physiol Pathophysiol Pharmacol. 2013;5:184–9.
   Google Scholar
• Tovar S, Nogueiras R, Tung LY, Castaneda TR, Vázquez MJ, Morris A, et al. Central administration of resistin promotes short-term satiety in rats. Eur J Endocrinol. 2005;153:R1–5.
   PubMed Web of Science ®Google Scholar
• Vázquez MJ, González CR, Varela L, Lage R, Tovar S, Sangiao-Alvarellos S, et al. Central resistin regulates hypothalamic and peripheral lipid metabolism in a nutritional-dependent fashion. Endocrinology. 2008;149:4534–43.
   PubMed Web of Science ®Google Scholar
• Feldman D. Evidence that brown adipose tissue is a glucocorticoid target organ. Endocrinology. 1978;103:2091–7.
   Google Scholar
• Viengchareun S, Penfornis P, Zennaro MC, Lombes M. Mineralocorticoid and glucocorticoid receptors inhibit UCP expression and function in brown adipocytes. Am J Physiol Endocrinol Metab. 2001;280:E640–9.
   PubMed Web of Science ®Google Scholar
• Soumano K, Desbiens S, Rabelo R, Bakopanos E, Camirand A, Silva JE. Glucocorticoids inhibit the transcriptional response of the uncoupling protein-1 gene to adrenergic stimulation in a brown adipose cell line. Mol Cell Endocrinol. 2000;165:7–15.
   Google Scholar
• Zennaro MC, Le Menuet D, Viengchareun S, Walker F, Ricquier D, Lombes M. Hibernoma development in transgenic mice identifies brown adipose tissue as a novel target of aldosterone action. J Clin Invest. 1998;101:1254–60.
   PubMed Web of Science ®Google Scholar
• Penfornis P, Viengchareun S, Le Menuet D, Cluzeaud F, Zennaro MC, Lombes M. The mineralocorticoid receptor mediates aldosterone- induced differentiation of T37i cells into brown adipocytes. Am J Physiol Endocrinol Metab. 2000;279:E386–94.
   PubMed Web of Science ®Google Scholar
• Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005;115:1627–35.
   PubMed Web of Science ®Google Scholar
• Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007;5:426–37.
   PubMed Web of Science ®Google Scholar
• Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab. 2007;5:415–25.
   PubMed Web of Science ®Google Scholar
• Galman C, Lundasen T, Kharitonenkov A, Bina HA, Eriksson M, Hafstrom I, et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab. 2008;8:169–74.
   PubMed Web of Science ®Google Scholar
• Hondares E, Rosell M, González FJ, Giralt M, Iglesias R, Villarroya F. Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab. 2010;11:206–12.
   PubMed Web of Science ®Google Scholar
• Hondares E, Iglesias R, Giralt A, González FJ, Giralt M, Mampel T, et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem. 2011;286:12983–90.
   PubMed Web of Science ®Google Scholar
• Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012;26:271–81.
   PubMed Web of Science ®Google Scholar
• Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. The bile acid membrane receptor TGR5: a valuable metabolic target. Dig Dis. 2011;29:37–44.
   PubMed Web of Science ®Google Scholar
• Angelin B, Larsson TE, Rudling M. Circulating fibroblast growth factors as metabolic regulators—a critical appraisal. Cell Metab. 2012;16:693–705.
   PubMed Web of Science ®Google Scholar
• Sarruf DA, Thaler JP, Morton GJ, German J, Fischer JD, Ogimoto K, et al. Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes. 2010; 59:1817–24.
   PubMed Web of Science ®Google Scholar
• Bookout AL, de Groot MH, Owen BM, Lee S, Gautron L, Lawrence HL, et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med. 2013;19: 1147–52.
   PubMed Web of Science ®Google Scholar
• Zhao Y, Dunbar JD, Kharitonenkov A. FGF21 as a therapeutic reagent. Adv Exp Med Biol. 2012;728:214–28.
   Google Scholar
• Chambers JB, Williams TD, Nakamura A, Henderson RP, Overton JM, Rashotte ME. Cardiovascular and metabolic responses of hypertensive and normotensive rats to one week of cold exposure. Am J Physiol Regul Integr Comp Physiol. 2000;279:R1486–94.
   Google Scholar
• Fregly MJ, Schechtman O. Direct blood pressure measurements in rats during abrupt exposure to, and removal from, cold air. Proc Soc Exp Biol Med. 1994;205:119–23.
   Google Scholar
• Sun Z, Cade JR, Fregly MJ, Rowland NE. Effect of chronic treatment with propranolol on the cardiovascular responses to chronic cold exposure. Physiol Behav. 1997;62:379–84.
   Google Scholar
• Moran MM, Roy RR, Wade CE, Corbin BJ, Grindeland RE. Size constraints of telemeters in rats. J Appl Physiol(1985). 1998;85: 1564–71.
   Google Scholar
• Stocks JM, Taylor NA, Tipton MJ, Greenleaf JE. Human physiological responses to cold exposure. Aviat Space Environ Med. 2004;75: 444–57.
   PubMed Web of Science ®Google Scholar
• Bianco AC, Maia AL, da Silva WS, Christoffolete MA. Adaptive activation of thyroid hormone and energy expenditure. Biosci Rep. 2005;25:191–208.
   PubMed Web of Science ®Google Scholar
• Laurberg P, Andersen S, Karmisholt J. Cold adaptation and thyroid hormone metabolism. Horm Metab Res. 2005;37:545–9.
   Web of Science ®Google Scholar
• Fuller CA, Horwitz BA, Horowitz JM. Shivering and nonshivering thermogenic responses of cold-exposed rats to hypothalamic warming. Am J Physiol. 1975;228:1519–24.
   PubMedGoogle Scholar
• Satinoff E, Valentino D, Teitelbaum P. Thermoregulatory cold-defense deficits in rats with preoptic/anterior hypothalamic lesions. Brain Res Bull. 1976;1:553–65.
   Google Scholar
• Imai-Matsumura K, Matsumura K, Nakayama T. Involvement of ventromedial hypothalamus in brown adipose tissue thermogenesis induced by preoptic cooling in rats. Jpn J Physiol. 1984;34:939–43.
   Google Scholar
• Scammell TE, Elmquist JK, Griffin JD, Saper CB. Ventromedial preoptic prostaglandin E2 activates fever-producing autonomic pathways. J Neurosci. 1996;16:6246–54.
   PubMed Web of Science ®Google Scholar
• Boulant JA. Role of the preoptic-anterior hypothalamus in thermoregulation and fever. Clin Infect Dis. 2000;31(Suppl 5):S157–61.
   PubMed Web of Science ®Google Scholar
• Bourova L, Pesanova Z, Novotny J, Bengtsson T, Svoboda P. Differentiation of cultured brown adipocytes is associated with a selective increase in the short variant of g(s)alpha protein. Evidence for higher functional activity of g(s)alphaS. Mol Cell Endocrinol. 2000;167: 23–31.
   Google Scholar
• Guieu JD, Hardy JD. Effects of heating and cooling of the spinal cord on preoptic unit activity. J Appl Physiol. 1970;29:675–83.
   Google Scholar
• Holt SJ, Wheal HV, York DA. Hypothalamic control of brown adipose tissue in Zucker lean and obese rats. Effect of electrical stimulation of the ventromedial nucleus and other hypothalamic centres. Brain Res. 1987;405:227–33.
   Google Scholar
• Thornhill J, Halvorson I. Activation of shivering and non-shivering thermogenesis by electrical stimulation of the lateral and medial preoptic areas. Brain Res. 1994;656:367–74.
   Google Scholar
• Boulant JA, Hardy JD. The effect of spinal and skin temperatures on the firing rate and thermosensitivity of preoptic neurones. J Physiol. 1974;240:639–60.
   PubMed Web of Science ®Google Scholar
• Hammel HT, Hardy JD, FUSCO MM. Thermoregulatory responses to hypothalamic cooling in unanesthetized dogs. Am J Physiol. 1960;198:481–6.
   PubMed Web of Science ®Google Scholar
• Nakamura K, Morrison SF. Preoptic mechanism for cold-defensive responses to skin cooling. J Physiol. 2008;586:2611–20.
   PubMed Web of Science ®Google Scholar
• Preston E, Triandafillou J, Haas N. Colchicine lesions of ventromedial hypothalamus: effects on regulatory thermogenesis in the rat. Pharmacol Biochem Behav. 1989;32:301–7.
   PubMed Web of Science ®Google Scholar
• Hogan S, Coscina DV, Himms-Hagen J. Brown adipose tissue of rats with obesity-inducing ventromedial hypothalamic lesions. Am J Physiol. 1982;243:E338–44.
   Google Scholar
• Virtue S, Masoodi M, Velagapudi V, Tan CY, Dale M, Suorti T, et al. Lipocalin prostaglandin D synthase and PPARgamma2 coordinate to regulate carbohydrate and lipid metabolism in vivo. PLoS One. 2012;7:e39512.
   Google Scholar
• Amir S, Schiavetto A. Injection of prostaglandin E2 into the anterior hypothalamic preoptic area activates brown adipose tissue thermogenesis in the rat. Brain Res. 1990;528:138–42.
   PubMed Web of Science ®Google Scholar
• Monda M, Sullo A, De Luca V, Viggiano A, Pellicano MP. Acute lesions of the ventromedial hypothalamus reduce sympathetic activation and thermogenic changes induced by PGE1. J Physiol Paris. 1997;91:285–90.
   PubMed Web of Science ®Google Scholar
• Steiner AA, Antunes-Rodrigues J, Branco LG. Role of preoptic second messenger systems (cAMP and cGMP) in the febrile response. Brain Res. 2002;944:135–45.
   Google Scholar
• Cao WH, Fan W, Morrison SF. Medullary pathways mediating specific sympathetic responses to activation of dorsomedial hypothalamus. Neuroscience. 2004;126:229–40.
   PubMed Web of Science ®Google Scholar
• Perkins MN, Rothwell NJ, Stock MJ, Stone TW. Activation of brown adipose tissue thermogenesis by the ventromedial hypothalamus. Nature. 1981;289:401–2.
   PubMed Web of Science ®Google Scholar
• Yoshida T, Bray GA. Catecholamine turnover in rats with ventromedial hypothalamic lesions. Am J Physiol. 1984;246:R558–65.
   Google Scholar
• Saito M, Minokoshi Y, Shimazu T. Ventromedial hypothalamic stimulation accelerates norepinephrine turnover in brown adipose tissue of rats. Life Sci. 1987;41:193–7.
   Google Scholar
• Kelly L, Bielajew C. Ventromedial hypothalamic regulation of brown adipose tissue. Neuroreport. 1991;2:41–4.
   Google Scholar
• Hugie T, Halvorson I, Thornhill J. Brown adipose tissue temperature responses following electrical stimulation of ventromedial hypothalamic and lateral preoptic areas or after norepinephrine infusion to Long Evans or Sprague-Dawley rats. Brain Res. 1992;575:57–62.
   Google Scholar
• Amir S. Intra-ventromedial hypothalamic injection of glutamate stimulates brown adipose tissue thermogenesis in the rat. Brain Res. 1990;511:341–4.
   Google Scholar
• Amir S, Schiavetto A, Pollock R. Insulin co-injection suppresses the thermogenic response to glutamate microinjection into the VMH in rats. Brain Res. 1990;527:326–9.
   Google Scholar
• Yoshimatsu H, Egawa M, Bray GA. Sympathetic nerve activity after discrete hypothalamic injections of L-glutamate. Brain Res. 1993; 601:121–8.
   PubMed Web of Science ®Google Scholar
• Sakaguchi T, Arase K, Bray GA. Effect of intrahypothalamic hydroxybutyrate on sympathetic firing rate. Metabolism. 1988;37:732–5.
   Google Scholar
• Sakaguchi T, Bray GA. Effect of norepinephrine, serotonin and tryptophan on the firing rate of sympathetic nerves. Brain Res. 1989;492:271–80.
   Google Scholar
• Bamshad M, Song CK, Bartness TJ. CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am J Physiol. 1999;276:R1569–78.
   PubMed Web of Science ®Google Scholar
• Cano G, Passerin AM, Schiltz JC, Card JP, Morrison SF, Sved AF. Anatomical substrates for the central control of sympathetic outflow to interscapular adipose tissue during cold exposure. J Comp Neurol. 2003;460:303–26.
   PubMed Web of Science ®Google Scholar
• Whittle AJ, Carobbio S, Martins L, Slawik M, Hondares E, Vázquez MJ, et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell. 2012;149:871–85.
   PubMed Web of Science ®Google Scholar
• Lindberg D, Chen P, Li C. Conditional viral tracing reveals that steroidogenic factor 1-positive neurons of the dorsomedial subdivision of the ventromedial hypothalamus project to autonomic centers of the hypothalamus and hindbrain. J Comp Neurol. 2013;521: 3167–90.
   Google Scholar
• Morrison SF. RVLM and raphe differentially regulate sympathetic outflows to splanchnic and brown adipose tissue. Am J Physiol. 1999;276:R962–73.
   PubMed Web of Science ®Google Scholar
• Shibata M, Uno T, Hashimoto M. Neurons in the lower midbrain tonically inhibit non-shivering thermogenesis through their influence on inferior olivary neurons in anesthetized rats. J Thermal Biol. 1999;24:365–8.
   Google Scholar
• Uno T, Shibata M. Role of inferior olive and thoracic IML neurons in nonshivering thermogenesis in rats. Am J Physiol Regul Integr Comp Physiol. 2001;280:R536–46.
   Google Scholar
• Morrison SF, Madden CJ, Tupone D. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab. 2014 Mar 12. [Epub ahead of print].
   Google Scholar
• Dimicco JA, Zaretsky DV. The dorsomedial hypothalamus: a new player in thermoregulation. Am J Physiol Regul Integr Comp Physiol. 2007;292:R47–63.
   PubMed Web of Science ®Google Scholar
• Kim KW, Zhao L, Donato J Jr, Kohno D, Xu Y, Elias CF, et al. Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus. Proc Natl Acad Sci U S A. 2011;108:10673–8.
   Google Scholar
• Jo YH. Endogenous BDNF regulates inhibitory synaptic transmission in the ventromedial nucleus of the hypothalamus. J Neurophysiol. 2012;107:42–9.
   Google Scholar
• Musatov S, Chen W, Pfaff DW, Mobbs CV, Yang XJ, Clegg DJ, et al. Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc Natl Acad Sci U S A. 2007;104:2501–6.
   PubMedGoogle Scholar
• Xu Y, Nedungadi TP, Zhu L, Sobhani N, Irani BG, Davis KE, et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 2011;14:453–65.
   PubMed Web of Science ®Google Scholar
• Martínez de Morentin PB, Whittle AJ, Ferno J, Nogueiras R, Diéguez C, Vidal-Puig A, et al. Nicotine induces negative energy balance through hypothalamic AMP-activated protein kinase. Diabetes. 2012;61:807–17.
   Google Scholar
• Seoane-Collazo P, de Morentin PB, Ferno J, Diéguez C, Nogueiras R, López M. Nicotine improves obesity and hepatic steatosis and er stress in diet-induced obese male rats. Endocrinology. 2014;155: 1679–89.
   Google Scholar
• Bernardis LL, Bellinger LL. The dorsomedial hypothalamic nucleus revisited: 1998 update. Proc Soc Exp Biol Med. 1998;218:284–306.
   PubMed Web of Science ®Google Scholar
• Bi S. Role of dorsomedial hypothalamic neuropeptide Y in energy homeostasis. Peptides. 2007;28:352–6.
   Google Scholar
• Zaretskaia MV, Zaretsky DV, Shekhar A, Dimicco JA. Chemical stimulation of the dorsomedial hypothalamus evokes non-shivering thermogenesis in anesthetized rats. Brain Res. 2002;928:113–25.
   Google Scholar
• Madden CJ, Morrison SF. Excitatory amino acid receptors in the dorsomedial hypothalamus mediate prostaglandin-evoked thermogenesis in brown adipose tissue. Am J Physiol Regul Integr Comp Physiol. 2004;286:R320–5.
   PubMedGoogle Scholar
• Dimicco JA, Abshire VM. Evidence for GABAergic inhibition of a hypothalamic sympathoexcitatory mechanism in anesthetized rats. Brain Res. 1987;402:1–10.
   Google Scholar
• Okamura H, Abitbol M, Julien JF, Dumas S, Berod A, Geffard M, et al. Neurons containing messenger RNA encoding glutamate decarboxylase in rat hypothalamus demonstrated by in situ hybridization, with special emphasis on cell groups in medial preoptic area, anterior hypothalamic area and dorsomedial hypothalamic nucleus. Neuroscience. 1990;39:675–99.
   Google Scholar
• Chen XM, Hosono T, Yoda T, Fukuda Y, Kanosue K. Efferent projection from the preoptic area for the control of non-shivering thermogenesis in rats. J Physiol. 1998;512(Pt 3):883–92.
   Google Scholar
• Osaka T. Blockade of prostaglandin E2-induced thermogenesis by unilateral microinjection of GABAA receptor antagonist into the preoptic area. Brain Res. 2008;1230:107–14.
   Google Scholar
• Cao WH, Morrison SF. Glutamate receptors in the raphe pallidus mediate brown adipose tissue thermogenesis evoked by activation of dorsomedial hypothalamic neurons. Neuropharmacology. 2006;51: 426–37.
   PubMed Web of Science ®Google Scholar
• Nakamura K, Matsumura K, Kobayashi S, Kaneko T. Sympathetic premotor neurons mediating thermoregulatory functions. Neurosci Res. 2005;51:1–8.
   PubMed Web of Science ®Google Scholar
• Enriori PJ, Sinnayah P, Simonds SE, Garcia RC, Cowley MA. Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance. J Neurosci. 2011;31:12189–97.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Kerman IA, Laque A, Nguyen P, Faouzi M, Louis GW, et al. Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and median preoptic area regulate sympathetic brown adipose tissue circuits. J Neurosci. 2011;31:1873–84.
   PubMed Web of Science ®Google Scholar
• Chao PT, Yang L, Aja S, Moran TH, Bi S. Knockdown of NPY expression in the dorsomedial hypothalamus promotes development of brown adipocytes and prevents diet-induced obesity. Cell Metab. 2011;13:573–83.
   Google Scholar
• Lee SJ, Verma S, Simonds SE, Kirigiti MA, Kievit P, Lindsley SR, et al. Leptin stimulates neuropeptide Y and cocaine amphetamine-regulated transcript coexpressing neuronal activity in the dorsomedial hypothalamus in diet-induced obese mice. J Neurosci. 2013;33:15306–17.
   PubMed Web of Science ®Google Scholar
• Cerri M, Morrison SF. Corticotropin releasing factor increases in brown adipose tissue thermogenesis and heart rate through dorsomedial hypothalamus and medullary raphe pallidus. Neuroscience. 2006;140:711–21.
   Google Scholar
• Zhang YH, Lu J, Elmquist JK, Saper CB. Lipopolysaccharide activates specific populations of hypothalamic and brainstem neurons that project to the spinal cord. J Neurosci. 2000;20:6578–86.
   PubMedGoogle Scholar
• Horn T, Wilkinson MF, Landgraf R, Pittman QJ. Reduced febrile responses to pyrogens after lesions of the hypothalamic paraventricular nucleus. Am J Physiol. 1994;267:R323–8.
   Google Scholar
• Caldeira JC, Franci CR, Pela IR. Bilateral lesion of hypothalamic paraventricular nucleus abolishes fever induced by endotoxin and bradykinin in rats. Ann N Y Acad Sci. 1998;856:294–7.
   Google Scholar
• Lu J, Zhang YH, Chou TC, Gaus SE, Elmquist JK, Shiromani P, et al. Contrasting effects of ibotenate lesions of the paraventricular nucleus and subparaventricular zone on sleep-wake cycle and temperature regulation. J Neurosci. 2001;21:4864–74.
   PubMed Web of Science ®Google Scholar
• Oldfield BJ, Giles ME, Watson A, Anderson C, Colvill LM, McKinley MJ. The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat. Neuroscience. 2002;110:515–26.
   PubMed Web of Science ®Google Scholar
• Bartness TJ, Vaughan CH, Song CK. Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond). 2010; 34(Suppl 1):S36–42.
   Google Scholar
• Vaughan CH, Bartness TJ. Anterograde transneuronal viral tract tracing reveals central sensory circuits from brown fat and sensory denervation alters its thermogenic responses. Am J Physiol Regul Integr Comp Physiol. 2012;302:R1049–58.
   Google Scholar
• Holt SJ, Wheal HV, York DA. Response of brown adipose tissue to electrical stimulation of hypothalamic centres in intact and adrenalectomized Zucker rats. Neurosci Lett. 1988;84:63–7.
   Google Scholar
• Madden CJ, Morrison SF. Neurons in the paraventricular nucleus of the hypothalamus inhibit sympathetic outflow to brown adipose tissue. Am J Physiol Regul Integr Comp Physiol. 2009;296:R831–43.
   PubMedGoogle Scholar
• Madden CJ, Tupone D, Cano G, Morrison SF. alpha2 Adrenergic receptor-mediated inhibition of thermogenesis. J Neurosci. 2013;33: 2017–28.
   PubMedGoogle Scholar
• Egawa M, Yoshimatsu H, Bray GA. Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats. Am J Physiol. 1991;260:R328–34.
   Google Scholar
• Billington CJ, Briggs JE, Harker S, Grace M, Levine AS. Neuropeptide Y in hypothalamic paraventricular nucleus: a center coordinating energy metabolism. Am J Physiol. 1994;266:R1765–70.
   PubMed Web of Science ®Google Scholar
• Kotz CM, Wang CF, Briggs JE, Levine AS, Billington CJ. Effect of NPY in the hypothalamic paraventricular nucleus on uncoupling proteins 1, 2, and 3 in the rat. Am J Physiol Regul Integr Comp Physiol. 2000;278:R494–8.
   Google Scholar
• Wang C, Billington CJ, Levine AS, Kotz CM. Effect of CART in the hypothalamic paraventricular nucleus on feeding and uncoupling protein gene expression. Neuroreport. 2000;11:3251–5.
   Google Scholar
• Russell SH, Small CJ, Sunter D, Morgan I, Dakin CL, Cohen MA, et al. Chronic intraparaventricular nuclear administration of orexin A in male rats does not alter thyroid axis or uncoupling protein-1 in brown adipose tissue. Regul Pept. 2002;104:61–8.
   Google Scholar
• LeFeuvre RA, Rothwell NJ, Stock MJ. Activation of brown fat thermogenesis in response to central injection of corticotropin releasing hormone in the rat. Neuropharmacology. 1987;26:1217–21.
   PubMed Web of Science ®Google Scholar
• Amir S. Stimulation of the paraventricular nucleus with glutamate activates interscapular brown adipose tissue thermogenesis in rats. Brain Res. 1990;508:152–5.
   PubMed Web of Science ®Google Scholar
• Yoshimatsu H, Egawa M, Bray GA. Effects of cholecystokinin on sympathetic activity to interscapular brown adipose tissue. Brain Res. 1992;597:298–303.
   Google Scholar
• Wang C, Bomberg E, Billington C, Levine A, Kotz CM. Brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus increases energy expenditure by elevating metabolic rate. Am J Physiol Regul Integr Comp Physiol. 2007;293:R992–1002.
   PubMed Web of Science ®Google Scholar
• Yasuda T, Masaki T, Sakata T, Yoshimatsu H. Hypothalamic neuronal histamine regulates sympathetic nerve activity and expression of uncoupling protein 1 mRNA in brown adipose tissue in rats. Neuroscience. 2004;125:535–40.
   PubMed Web of Science ®Google Scholar
• Kotz CM, Wang C, Levine AS, Billington CJ. Urocortin in the hypothalamic PVN increases leptin and affects uncoupling proteins-1 and -3 in rats. Am J Physiol Regul Integr Comp Physiol. 2002;282: R546–51.
   Google Scholar
• Kong W, Stanley S, Gardiner J, Abbott C, Murphy K, Seth A, et al. A role for arcuate cocaine and amphetamine-regulated transcript in hyperphagia, thermogenesis, and cold adaptation. FASEB J. 2003; 17:1688–90.
   PubMed Web of Science ®Google Scholar
• Bhatnagar S, Meaney MJ, Amir S. The effects of prostaglandin E2 injected into the paraventricular nucleus of the hypothalamus on brown adipose tissue thermogenesis in spontaneously hypertensive rats. Brain Res. 1993;613:285–7.
   Google Scholar
• Kotz CM, Briggs JE, Grace MK, Levine AS, Billington CJ. Divergence of the feeding and thermogenic pathways influenced by NPY in the hypothalamic PVN of the rat. Am J Physiol. 1998;275:R471–7.
   Google Scholar
• Fan W, Morrison SF, Cao WH, Yu P. Thermogenesis activated by central melanocortin signaling is dependent on neurons in the rostral raphe pallidus (rRPa) area. Brain Res. 2007;1179:61–9.
   Google Scholar
• Song CK, Vaughan CH, Keen-Rhinehart E, Harris RB, Richard D, Bartness TJ. Melanocortin-4 receptor mRNA expressed in sympathetic outflow neurons to brown adipose tissue: neuroanatomical and functional evidence. Am J Physiol Regul Integr Comp Physiol. 2008; 295:R417–28.
   PubMed Web of Science ®Google Scholar
• Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T, et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell. 2005;123:493–505.
   PubMed Web of Science ®Google Scholar
• Skibicka KP, Grill HJ. Hypothalamic and hindbrain melanocortin receptors contribute to the feeding, thermogenic, and cardiovascular action of melanocortins. Endocrinology. 2009;150:5351–61.
   Google Scholar
• Elmquist JK, Coppari R, Balthasar N, Ichinose M, Lowell BB. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol. 2005;493:63–71.
   PubMed Web of Science ®Google Scholar
• López M, Tovar S, Vázquez MJ, Williams LM, Diéguez C. Peripheral tissue-brain interactions in the regulation of food intake. Proc Nutr Soc. 2007;66:131–55.
   Google Scholar
• Abizaid A, Horvath TL. Brain circuits regulating energy homeostasis. Regul Pept. 2008;149:3–10.
   PubMedGoogle Scholar
• Lage R, Diéguez C, Vidal-Puig A, López M. AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med. 2008; 14:539–49.
   PubMed Web of Science ®Google Scholar
• Kleinridders A, Konner AC, Bruning JC. CNS-targets in control of energy and glucose homeostasis. Curr Opin Pharmacol. 2009;9: 794–804.
   Google Scholar
• Diéguez C, Vázquez MJ, Romero A, López M, Nogueiras R. Hypothalamic control of lipid metabolism: focus on leptin, ghrelin and melanocortins. Neuroendocrinology. 2011;94:1–11.
   PubMed Web of Science ®Google Scholar
• Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, Webster Z, et al. Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J. 2005;19:1680–2.
   PubMed Web of Science ®Google Scholar
• Shi YC, Lau J, Lin Z, Zhang H, Zhai L, Sperk G, et al. Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab. 2013;17: 236–48.
   Google Scholar
• Butler AA, Cone RD. The melanocortin receptors: lessons from knockout models. Neuropeptides. 2002;36:77–84.
   Google Scholar
• Farooqi S, O’Rahilly S. Genetics of obesity in humans. Endocr Rev. 2006;27:710–18.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Kilroy GE, Henagan TM, Prpic-Uhing V, Richards WG, Bannon AW, et al. Targeted deletion of melanocortin receptor subtypes 3 and 4, but not CART, alters nutrient partitioning and compromises behavioral and metabolic responses to leptin. FASEB J. 2005;19: 1482–91.
   Google Scholar
• Harlan SM, Morgan DA, Agassandian K, Guo DF, Cassell MD, Sigmund CD, et al. Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ Res. 2011;108:808–12.
   Google Scholar
• Kong D, Tong Q, Ye C, Koda S, Fuller PM, Krashes MJ, et al. GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell. 2012;151:645–57.
   PubMed Web of Science ®Google Scholar
• Van der Zee CE. Hypothalamic plasticity of neuropeptide Y is lacking in brain-type creatine kinase double knockout mice with defective thermoregulation. Eur J Pharmacol. 2013;719:137–44.
   Google Scholar
• Huang H, Kong D, Byun KH, Ye C, Koda S, Lee DH, et al. Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling. Nat Neurosci. 2012;15:1391–8.
   PubMed Web of Science ®Google Scholar
• Tong Q, Ye CP, Jones JE, Elmquist JK, Lowell BB. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci. 2008;11:998–1000.
   PubMed Web of Science ®Google Scholar
• Hardie DG, Carling D. The AMP-activated protein kinase—fuel gauge of the mammalian cell?Eur J Biochem. 1997;246:259–73.
   PubMedGoogle Scholar
• Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1:15–25.
   PubMed Web of Science ®Google Scholar
• Woods SC, Seeley RJ, Cota D. Regulation of food intake through hypothalamic signaling networks involving mTOR. Annu Rev Nutr. 2008;28:295–311.
   PubMed Web of Science ®Google Scholar
• Blanco Martínez de Morentin P, González CR, Saha AK, Martins L, Diéguez C, Vidal-Puig A, et al. Hypothalamic AMP-activated protein kinase as a mediator of whole body energy balance. Rev Endocr Metab Disord. 2011;12:127–40.
   PubMed Web of Science ®Google Scholar
• Martínez de Morentin PB, Martínez-Sanchez N, Roa J, Ferno J, Nogueiras R, Tena-Sempere M, et al. Hypothalamic mTOR: the rookie energy sensor. Curr Mol Med. 2014;14:3–21.
   PubMed Web of Science ®Google Scholar
• Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004;428: 569–74.
   PubMed Web of Science ®Google Scholar
• López M, Lage R, Saha AK, Perez-Tilve D, Vázquez MJ, Varela L, et al. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab. 2008;7:389–99.
   PubMed Web of Science ®Google Scholar
• Andrews ZB, Liu ZW, Walllingford N, Erion DM, Borok E, Friedman JM, et al. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature. 2008;454:846–51.
   PubMed Web of Science ®Google Scholar
• Xue B, Pulinilkunnil T, Murano I, Bence KK, He H, Minokoshi Y, et al. Neuronal protein tyrosine phosphatase 1B deficiency results in inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues. Mol Cell Biol. 2009;29:4563–73.
   PubMedGoogle Scholar
• Tanida M, Yamamoto N, Shibamoto T, Rahmouni K. Involvement of hypothalamic AMP-activated protein kinase in leptin-induced sympathetic nerve activation. PLoS One. 2013;8:e56660.
   Google Scholar
• Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92:1.
   PubMed Web of Science ®Google Scholar
• de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A. 1998;95:322–7.
   PubMed Web of Science ®Google Scholar
• López M, Tena-Sempere M, Diéguez C. Cross-talk between orexins (hypocretins) and the neuroendocrine axes (hypothalamic-pituitary axes). Front Neuroendocrinol. 2010;31:113–27.
   Web of Science ®Google Scholar
• Cerri M, Morrison SF. Activation of lateral hypothalamic neurons stimulates brown adipose tissue thermogenesis. Neuroscience. 2005;135:627–38.
   Google Scholar
• López M, Nogueiras R, Tena-Sempere M, Diéguez C. Orexins (hypocretins) actions on the GHRH/somatostatin-GH axis. Acta Physiol (Oxf). 2010;198:325–34.
   Google Scholar
• Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron. 2001;30:345–54.
   PubMed Web of Science ®Google Scholar
• Teske JA, Levine AS, Kuskowski M, Levine JA, Kotz CM. Elevated hypothalamic orexin signaling, sensitivity to orexin A, and spontaneous physical activity in obesity-resistant rats. Am J Physiol Regul Integr Comp Physiol. 2006;291:R889–99.
   Google Scholar
• Sellayah D, Bharaj P, Sikder D. Orexin is required for brown adipose tissue development, differentiation, and function. Cell Metab. 2011;14:478–90.
   Google Scholar
• Morrison SF, Madden CJ, Tupone D. Central control of brown adipose tissue thermogenesis. Front Endocrinol (Lausanne). 2012;3:pii: 00005.
   PubMedGoogle Scholar
• Madden CJ, Tupone D, Morrison SF. Orexin modulates brown adipose tissue thermogenesis. Biomol Concepts. 2012;3:381–6.
   Google Scholar
• Sellayah D, Sikder D. Orexin receptor-1 mediates brown fat developmental differentiation. Adipocyte. 2012;1:58–63.
   PubMedGoogle Scholar
• Berthoud HR, Patterson LM, Sutton GM, Morrison C, Zheng H. Orexin inputs to caudal raphe neurons involved in thermal, cardiovascular, and gastrointestinal regulation. Histochem Cell Biol. 2005; 123:147–56.
   PubMedGoogle Scholar
• Monda M, Viggiano AN, Viggiano A, Viggiano E, Lanza A, De Luca V. Hyperthermic reactions induced by orexin A: role of the ventromedial hypothalamus. Eur J Neurosci. 2005;22:1169–75.
   Google Scholar
• Yasuda T, Masaki T, Kakuma T, Hara M, Nawata T, Katsuragi I, et al. Dual regulatory effects of orexins on sympathetic nerve activity innervating brown adipose tissue in rats. Endocrinology. 2005;146:2744–8.
   Google Scholar
• Morrison SF, Madden CJ, Tupone D. An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. Adipocyte. 2012;1:116–20.
   PubMedGoogle Scholar
• Tupone D, Madden CJ, Cano G, Morrison SF. An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. J Neurosci. 2011;31:15944–55.
   PubMed Web of Science ®Google Scholar
• Monda M, Viggiano A, Viggiano A, Fuccio F, De Luca V. Injection of orexin A into the diagonal band of Broca induces sympathetic and hyperthermic reactions. Brain Res. 2004;1018:265–71.
   Google Scholar
• Zhang W, Sunanaga J, Takahashi Y, Mori T, Sakurai T, Kanmura Y, et al. Orexin neurons are indispensable for stress-induced thermogenesis in mice. J Physiol. 2010;588:4117–29.
   Google Scholar
• Sellayah D, Sikder D. Orexin restores aging-related brown adipose tissue dysfunction in male mice. Endocrinology. 2014;155:485–501.
   Google Scholar
• Stefan N, Pfannenberg C, Haring HU. The importance of brown adipose tissue. N Engl J Med. 2009;361:416–17.
   Google Scholar
• Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009;58:1526–31.
   PubMed Web of Science ®Google Scholar
• Carter S, Caron A, Richard D, Picard F. Role of leptin resistance in the development of obesity in older patients. Clin Interv Aging. 2013;8: 829–44.
   PubMed Web of Science ®Google Scholar
• Slawik M, Vidal-Puig AJ. Lipotoxicity, overnutrition and energy metabolism in aging. Ageing Res Rev. 2006;5:144–64.
   PubMed Web of Science ®Google Scholar
• Lin L, Saha PK, Ma X, Henshaw IO, Shao L, Chang BH, et al. Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues. Aging Cell. 2011;10:996–1010.
   Web of Science ®Google Scholar
• Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, et al. Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol Rev. 2012;92:1479–514.
   PubMed Web of Science ®Google Scholar
• Christian BE, Shadel GS. Aging: it's SIRTainly possible to restore mitochondrial dysfunction. Curr Biol. 2014;24:R206–8.
   Google Scholar
• Townsend KL, Suzuki R, Huang TL, Jing E, Schulz TJ, Lee K, et al. Bone morphogenetic protein 7 (BMP7) reverses obesity and regulates appetite through a central mTOR pathway. FASEB J. 2012;26: 2187–96.
   Google Scholar
• Schulz TJ, Huang TL, Tran TT, Zhang H, Townsend KL, Shadrach JL, et al. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc Natl Acad Sci U S A. 2011; 108:143–8.
   PubMed Web of Science ®Google Scholar
• Lockie SH, Stefanidis A, Oldfield BJ, Perez-Tilve D. Brown adipose tissue thermogenesis in the resistance to and reversal of obesity: a potential new mechanism contributing to the metabolic benefits of proglucagon-derived peptides. Adipocyte. 2013;2:196–200.
   PubMedGoogle Scholar
• Lockie SH, Heppner KM, Chaudhary N, Chabenne JR, Morgan DA, Veyrat-Durebex C, et al. Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes. 2012;61:2753–62.
   PubMed Web of Science ®Google Scholar
• Ogawa A, Harris V, McCorkle SK, Unger RH, Luskey KL. Amylin secretion from the rat pancreas and its selective loss after streptozotocin treatment. J Clin Invest. 1990;85:973–6.
   PubMed Web of Science ®Google Scholar
• Roth JD, Hughes H, Kendall E, Baron AD, Anderson CM. Antiobesity effects of the beta-cell hormone amylin in diet-induced obese rats: effects on food intake, body weight, composition, energy expenditure, and gene expression. Endocrinology. 2006;147: 5855–64.
   PubMed Web of Science ®Google Scholar
• Wielinga PY, Lowenstein C, Muff S, Munz M, Woods SC, Lutz TA. Central amylin acts as an adiposity signal to control body weight and energy expenditure. Physiol Behav. 2010;101:45–52.
   Google Scholar
• Zhang Z, Liu X, Morgan DA, Kuburas A, Thedens DR, Russo AF, et al. Neuronal receptor activity-modifying protein 1 promotes energy expenditure in mice. Diabetes. 2011;60:1063–71.
   Google Scholar
• Fernandes-Santos C, Zhang Z, Morgan DA, Guo DF, Russo AF, Rahmouni K. Amylin acts in the central nervous system to increase sympathetic nerve activity. Endocrinology. 2013;154:2481–8.
   Google Scholar
• Roth JD, Maier H, Chen S, Roland BL. Implications of amylin receptor agonism: integrated neurohormonal mechanisms and therapeutic applications. Arch Neurol. 2009;66:306–10.
   PubMedGoogle Scholar
• López M, Nogueiras R. Firing up brown fat with brain amylin. Endocrinology. 2013;154:2263–5.
   Google Scholar
• Smith SR, Aronne LJ, Burns CM, Kesty NC, Halseth AE, Weyer C. Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes Care. 2008;31: 1816–23.
   PubMed Web of Science ®Google Scholar
• Ravussin E, Smith SR, Mitchell JA, Shringarpure R, Shan K, Maier H, et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring). 2009;17:1736–43.
   PubMed Web of Science ®Google Scholar
• Sadry SA, Drucker DJ. Emerging combinatorial hormone therapies for the treatment of obesity and T2DM. Nat Rev Endocrinol. 2013;9: 425–33.
   PubMed Web of Science ®Google Scholar
• Konczol K, Pinter O, Ferenczi S, Varga J, Kovacs K, Palkovits M, et al. Nesfatin-1 exerts long-term effect on food intake and body temperature. Int J Obes (Lond). 2012;36:1514–21.
   Google Scholar
• Cardinal P, Bellocchio L, Clark S, Cannich A, Klugmann M, Lutz B, et al. Hypothalamic CB1 cannabinoid receptors regulate energy balance in mice. Endocrinology. 2012;153:4136–43.
   Google Scholar
• Jung KM, Clapper JR, Fu J, D’Agostino G, Guijarro A, Thongkham D, et al. 2-arachidonoylglycerol signaling in forebrain regulates systemic energy metabolism. Cell Metab. 2012;15:299–310.
   PubMed Web of Science ®Google Scholar