Abstract
β-adrenergic receptors (βARs) are well established for conveying the signal from catecholamines to adipocytes. Acting through the second messenger cyclic adenosine monophosphate (cAMP) they stimulate lipolysis and also increase the activity of brown adipocytes and the ‘browning’ of adipocytes within white fat depots (so-called ‘brite’ or ‘beige’ adipocytes). Brown adipose tissue mitochondria are enriched with uncoupling protein 1 (UCP1), which is a regulated proton channel that allows the dissipation of chemical energy in the form of heat. The discovery of functional brown adipocytes in humans and inducible brown-like (‘beige’ or ‘brite’) adipocytes in rodents have suggested that recruitment and activation of these thermogenic adipocytes could be a promising strategy to increase energy expenditure for obesity therapy. More recently, the cardiac natriuretic peptides and their second messenger cyclic guanosine monophosphate (cGMP) have gained attention as a parallel signaling pathway in adipocytes, with some unique features. In this review, we begin with some important historical work that touches upon the regulation of brown adipocyte development and physiology. We then provide a synopsis of some recent advances in the signaling cascades from β-adrenergic agonists and natriuretic peptides to drive thermogenic gene expression in the adipocytes and how these two pathways converge at a number of unexpected points. Finally, moving from the physiologic hormonal signaling, we discuss yet another level of control downstream of these signals: the growing appreciation of the emerging roles of non-coding RNAs as important regulators of brown adipocyte formation and function. In this review, we discuss new developments in our understanding of the signaling mechanisms and factors including new secreted proteins and novel non-coding RNAs that control the function as well as the plasticity of the brown/beige adipose tissue as it responds to the energy needs and environmental conditions of the organism.
Author Statement
Research funding: Authors state no funding involved.
Conflict of interest: Authors state no conflict of interest.
Informed consent: Informed consent is not applicable.
Ethical approval: The conducted research is not related to either human or animals use.
[1] 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.Search in Google Scholar
[2] Huttunen P, Hirvonen J, Kinnula V. The occurrence of brown adipose tissue in outdoor workers. Eur J Appl Physiol Occup Physiol. 1981;46:339–45.Search in Google Scholar
[3] 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.Search in Google Scholar
[4] 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.Search in Google Scholar
[5] 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.Search in Google Scholar
[6] Orava J, Nuutila P, Noponen T, Parkkola R, Viljanen T, Enerback S, et al. Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans. Obesity (Silver Spring). 2013;21:2279–87.Search in Google Scholar
[7] Lee P, Smith S, Linderman J, Courville AB, Brychta RJ, Dieckmann W, et al. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes. 2014;63:3686–98.Search in Google Scholar
[8] Hanssen MJ, van der Lans AA, Brans B, Hoeks J, Jardon KM, Schaart G, et al. Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes. 2016;65:1179–89.Search in Google Scholar
[9] Koskensalo K, Raiko J, Saari T, Saunavaara V, Eskola O, Nuutila P, et al. Human brown adipose tissue temperature and fat fraction are related to its metabolic activity. J Clin Endocrinol Metab. 2017;102:1200–7.Search in Google Scholar
[10] Smith RE, Hoijer DJ. Metabolism and cellular function in cold acclimation. Physiol Rev. 1962;42:60–142.Search in Google Scholar
[11] Smith RE, Roberts JC. Thermogenesis of brown adipose tissue in cold-acclimated rats. Am J Physiol. 1964;206:143–8.Search in Google Scholar
[12] Bartness TJ, Song CK. Thematic review series: adipocyte biology. Sympathetic and sensory innervation of white adipose tissue. J Lipid Res. 2007;48:1655–72.Search in Google Scholar
[13] Bartness TJ, Ryu V. Neural control of white, beige and brown adipocytes. Int J Obes Suppl. 2015;5:S35–9.Search in Google Scholar
[14] Bartness TJ, Vaughan CH, Song CK. Sympathetic and sensory innervation of brown adipose tissue. Int J Obes. 2010;34:S36–42.Search in Google Scholar
[15] Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elia E, Kessler SH, Kahn PA, et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 2015;21:33–8.Search in Google Scholar
[16] Qiu Y, Nguyen KD, Odegaard JI, Cui X, Tian X, Locksley RM, et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell. 2014;157:1292–308.Search in Google Scholar
[17] Nguyen KD, Qiu Y, Cui X, Goh YP, Mwangi J, David T, et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature. 2011;480:104–8.Search in Google Scholar
[18] Fischer K, Ruiz HH, Jhun K, Finan B, Oberlin DJ, van der Heide V, et al. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med. 2017;23:623–30.Search in Google Scholar
[19] Kim SN, Jung YS, Kwon HJ, Seong JK, Granneman JG, Lee YH. Sex differences in sympathetic innervation and browning of white adipose tissue of mice. Biol Sex Differ. 2016;7:67.Search in Google Scholar
[20] Xue B, Rim JS, Hogan JC, Coulter AA, Koza RA, Kozak LP. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J Lipid Res. 2007;48:41–51.Search in Google Scholar
[21] Vitali A, Murano I, Zingaretti MC, Frontini A, Ricquier D, Cinti S. The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes. J Lipid Res. 2012;53:619–29.Search in Google Scholar
[22] Lafontan M, Berlan M. Fat cell adrenergic receptors and the control of white and brown fat cell function. J Lipid Res. 1993;34:1057–91.Search in Google Scholar
[23] Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Muller CE. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol Rev. 2011;63:1–34.Search in Google Scholar
[24] Uchida Y, Nomoto T. Intravenously infused adenosine increases the blood flow to brown adipose tissue in rats. Eur J Pharmacol. 1990;184:223–31.Search in Google Scholar
[25] Gnad T, Scheibler S, von Kügelgen I, Scheele C, Kilić A, Glöde A, et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature. 2014;516:395–9.Search in Google Scholar
[26] 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.Search in Google Scholar
[27] Cao W, Daniel KW, Robidoux J, Puigserver P, Medvedev AV, Bai X, 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. 2004;24:3057–67.Search in Google Scholar
[28] Robidoux J, Cao W, Quan H, Daniel KW, Moukdar F, Bai X, et al. Selective activation of mitogen-activated protein (MAP) kinase kinase 3 and p38{alpha} MAP kinase is essential for cyclic AMP-dependent UCP1 expression in adipocytes. Mol Cell Biol. 2005;25:5466–79.Search in Google Scholar
[29] 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.Search in Google Scholar
[30] Sellayah D, Bharaj P, Sikder D. Orexin is required for brown adipose tissue development, differentiation, and function. Cell Metab. 2011;14:478–90.Search in Google Scholar
[31] Whittle AJ, Carobbio S, Martins L, Slawik M, Hondares E, Vazquez MJ, et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell. 2012;149:871–85.Search in Google Scholar
[32] 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.Search in Google Scholar
[33] Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessì-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.Search in Google Scholar
[34] de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci. 1981;28:89–94.Search in Google Scholar
[35] Waldman SA, Rapoport RM, Murad F. Atrial natriuretic factor selectively activates particulate guanylate cyclase and elevates cyclic GMP in rat tissues. J Biol Chem. 1984;259:14332–4.Search in Google Scholar
[36] Chinkers M, Garbers DL, Chang MS, Lowe DG, Chin HM, Goeddel DV, et al. A membrane form of guanylate cyclase is an atrial natriuretic peptide receptor. Nature. 1989;338:78–83.Search in Google Scholar
[37] Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev. 2006;27:47–72.Search in Google Scholar
[38] Potter LR. Natriuretic peptide metabolism, clearance and degradation. FEBS J. 2011;278:1808–17.Search in Google Scholar
[39] Murthy KS, Teng BQ, Zhou H, Jin JG, Grider JR, Makhlouf GM. G(i-1)/G(i-2)-dependent signaling by single-transmembrane natriuretic peptide clearance receptor. Am J Physiol Gastrointest Liver Physiol. 2000;278:G974–80.Search in Google Scholar
[40] Pagano M, Anand-Srivastava MB. Cytoplasmic domain of natriuretic peptide receptor C constitutes Gi activator sequences that inhibit adenylyl cyclase activity. J Biol Chem. 2001;276:22064–70.Search in Google Scholar
[41] Nishikimi T, Iemura-Inaba C, Akimoto K, Ishikawa K, Koshikawa S, Matsuoka H. Stimulatory and Inhibitory regulation of lipolysis by the NPR-A/cGMP/PKG and NPR-C/G(i) pathways in rat cultured adipocytes. Regul Pept. 2009;153:56–63.Search in Google Scholar
[42] Sarzani R, Dessi-Fulgheri P, Paci VM, Espinosa E, Rappelli A. Expression of natriuretic peptide receptors in human adipose and other tissues. J Endocrinol Invest. 1996;19:581–5.Search in Google Scholar
[43] Sengenes C, Berlan M, De Glisezinski I, Lafontan M, Galitzky J. Natriuretic peptides: a new lipolytic pathway in human adipocytes. FASEB J. 2000;14:1345–51.Search in Google Scholar
[44] Birkenfeld AL, Boschmann M, Moro C, Adams F, Heusser K, Tank J, et al. Beta-adrenergic and atrial natriuretic peptide interactions on human cardiovascular and metabolic regulation. J Clin Endocrinol Metab. 2006;91:5069–75.Search in Google Scholar
[45] Collins S. A heart-adipose tissue connection in the regulation of energy metabolism. Nat Rev Endocrinol. 2014;10:157–63.Search in Google Scholar
[46] Wang TJ, Larson MG, Keyes MJ, Levy D, Benjamin EJ, Vasan RS. Association of plasma natriuretic peptide levels with metabolic risk factors in ambulatory individuals. Circulation. 2007;115:1345–53.Search in Google Scholar
[47] Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Wilson PW, et al. Impact of obesity on plasma natriuretic peptide levels. Circulation. 2004;109:594–600.Search in Google Scholar
[48] Kovacova Z, Tharp WG, Liu D, Wei W, Xie H, Collins S, et al. Adipose tissue natriuretic peptide receptor expression is related to insulin sensitivity in obesity and diabetes. Obesity (Silver Spring). 2016;24:820–8.Search in Google Scholar
[49] Clerico A, Giannoni A, Vittorini S, Emdin M. The paradox of low BNP levels in obesity. Heart Fail Rev. 2012;17:81–96.Search in Google Scholar
[50] Arora P, Reingold J, Baggish A, Guanaga DP, Wu C, Ghorbani A, et al. Weight loss, saline loading, and the natriuretic peptide system. J Am Heart Assoc. 2015;4:e001265.Search in Google Scholar
[51] Ramos HR, Birkenfeld AL, de Bold AJ. INTERACTING DISCIPLINES: Cardiac natriuretic peptides and obesity: perspectives from an endocrinologist and a cardiologist. Endocr Connect. 2015;4:R25–36.Search in Google Scholar
[52] Das SR, Drazner MH, Dries DL, Vega GL, Stanek HG, Abdullah SM, et al. Impact of body mass and body composition on circulating levels of natriuretic peptides: results from the Dallas Heart Study. Circulation. 2005;112:2163–8.Search in Google Scholar
[53] Sengenes C, Zakaroff-Girard A, Moulin A, Berlan M, Bouloumie A, Lafontan M, et al. Natriuretic peptide-dependent lipolysis in fat cells is a primate specificity. Am J Physiol Regul Integr Comp Physiol. 2002;283:R257–65.Search in Google Scholar
[54] Matsukawa N, Grzesik WJ, Takahashi N, Pandey KN, Pang S, Yamauchi M, et al. The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. Proc Natl Acad Sci USA. 1999;96:7403–8.Search in Google Scholar
[55] Wu W, Shi F, Liu D, Ceddia RP, Gaffin R, Wei W, et al. Enhancing natriuretic peptide signaling in adipose tissue, but not in muscle, protects against diet-induced obesity and insulin resistance. Sci Signal. 2017;10:eaam6870.Search in Google Scholar
[56] Huang K, Fingar DC. Growing knowledge of the mTOR signaling network. Semin Cell Dev Biol. 2014;36:79–90.Search in Google Scholar
[57] Liu D, Bordicchia M, Zhang C, Fang H, Wei W, Li JL, et al. Activation of mTORC1 is essential for β-adrenergic stimulation of adipose browning. J Clin Invest. 2016;126:1704–16.Search in Google Scholar
[58] Thomas G, Hall MN. TOR signalling and control of cell growth. Curr Opin Cell Biol. 1997;9:782–7.Search in Google Scholar
[59] Wada S, Neinast M, Jang C, Ibrahim YH, Lee G, Babu A, et al. The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue. Genes Dev. 2016;30:2551–64.Search in Google Scholar
[60] Mori MA, Thomou T, Boucher J, Lee KY, Lallukka S, Kim JK, et al. Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J Clin Invest. 2014;124:3339–51.Search in Google Scholar
[61] Kim HJ, Cho H, Alexander R, Patterson HC, Gu M, Lo KA, et al. MicroRNAs are required for the feature maintenance and differentiation of brown adipocytes. Diabetes. 2014;63:4045–56.Search in Google Scholar
[62] Trajkovski M, Ahmed K, Esau CC, Stoffel M. MyomiR-133 regulates brown fat differentiation through Prdm16. Nat Cell Biol. 2012;14:1330–5.Search in Google Scholar
[63] Yin H, Pasut A, Soleimani VD, Bentzinger CF, Antoun G, Thorn S, et al. MicroRNA-133 controls brown adipose determination in skeletal muscle satellite cells by targeting Prdm16. Cell Metab. 2013;17:210–24.Search in Google Scholar
[64] Liu W, Bi P, Shan T, Yang X, Yin H, Wang YX, et al. miR-133a regulates adipocyte browning in vivo. PLoS Genet. 2013;9:e1003626.Search in Google Scholar
[65] 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. 2012;10:e1001314.Search in Google Scholar
[66] Chen Y, Siegel F, Kipschull S, Haas B, Frohlich H, Meister G, et al. miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit. Nat Commun. 2013;4:1769.Search in Google Scholar
[67] Pan D, Mao C, Quattrochi B, Friedline RH, Zhu LJ, Jung DY, et al. MicroRNA-378 controls classical brown fat expansion to counteract obesity. Nat Commun. 2014;5:4725.Search in Google Scholar
[68] Bonasio R, Shiekhattar R. Regulation of transcription by long noncoding RNAs. Annu Rev Genet. 2014;48:433–55.Search in Google Scholar
[69] Sun L, Goff LA, Trapnell C, Alexander R, Lo KA, Hacisuleyman E, et al. Long noncoding RNAs regulate adipogenesis. Proc Natl Acad Sci USA. 2013;110:3387–92.Search in Google Scholar
[70] Hacisuleyman E, Goff LA, Trapnell C, Williams A, Henao-Mejia J, Sun L, et al. Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre. Nat Struct Mol Biol. 2014;21:198–206.Search in Google Scholar
[71] Zhao XY, Li S, Wang GX, Yu Q, Lin JD. A long noncoding RNA transcriptional regulatory circuit drives thermogenic adipocyte differentiation. Mol Cell. 2014;55:372–82.Search in Google Scholar
[72] Alvarez-Dominguez JR, Bai Z, Xu D, Yuan B, Lo KA, Yoon MJ, et al. De novo reconstruction of adipose tissue transcriptomes reveals long non-coding RNA regulators of brown adipocyte development. Cell Metab. 2015;21:764–76.Search in Google Scholar
[73] Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet. 2011;378:815–25.Search in Google Scholar
[74] Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell. 2007;131:242–56.Search in Google Scholar
[75] Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148:852–71.Search in Google Scholar
[76] Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18:363–74.Search in Google Scholar
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