Abstract
Adrenergic receptor signaling in adipocytes controls not only the hydrolysis of triglycerides as fuel for other organs but is also a driver of brown adipocyte thermogenesis and energy consumption. As the appearance of these mitochondria-rich, thermogenically active cells in ‘white’ adipocyte depots is correlated with resistance to overnutrition and glucose intolerance, the molecular basis of their genesis and metabolic activity needs to be understood. β-adrenergic receptors regulate the enzymatic machinery for lipolysis and fuel utilization. They also coordinately stimulate the transcription of genes that support the specific functions of white and brown adipocytes. They accomplish this through the activation of a network of signaling pathways that include cAMP-dependent protein kinase and members of the mitogen-activated protein kinase family. In brown adipocytes, these kinases control the transcription of nuclear factors such as peroxisome proliferator-activated receptor-γ coactivator-1s, as well as other molecules discovered to respond to adrenergic signals, to increase mitochondrial biogenesis and uncoupling protein-1 (UCP1) expression. However, it is also important to understand the mechanisms that may actively repress these energy-wasting processes. Toward that end, we provide evidence for an important role for the nuclear receptor LXRα as a cAMP- and oxysterol-dependent transcriptional repressor of the Ucp1 gene. Adipocytes from LXRα-null mice have increased expression of most ‘markers’ of brown adipocytes, increased mitochondrial mass and uncoupled respiration. These studies reveal potential new targets and directions for controlling the relative levels of white versus brown adipocytes as a means of metabolic fuel utilization in the struggle against obesity and related metabolic diseases.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Cao W, Robidoux J, Puigserver P, Daniel KW, Medvedev AV, Bai X et al. p38 MAP kinase is the central regulator of cAMP-dependent transcription of the brown fat uncoupling protein-1 gene. Mol Cell Biol 2004; 24: 3057–3067.
Robidoux J, Kumar N, Daniel KW, Moukdar F, Cyr M, Medvedev AV et al. Maximal beta3-adrenergic regulation of lipolysis involves Src and epidermal growth factor receptor-dependent ERK1/2 activation. J Biol Chem 2006; 281: 37794–37802.
Kumar N, Robidoux J, Daniel KW, Guzman G, Floering LM, Collins S . Requirement of vimentin filament assembly for beta3-adrenergic receptor activation of ERK MAP kinase and lipolysis. J Biol Chem 2007; 282: 9244–9250.
Thomas SA, Palmiter RD . Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline. Nature 1997; 397: 94–97.
Bachman ES, Dhillon H, Zhang CY, Cinti S, Bianco AC, Kobilka BK et al. betaAR signaling required for diet-induced thermogenesis and obesity resistance. Science 2002; 297: 843–845.
Depocas F, Behrens WA, Foster DO . Noradrenaline-induced calorigenesis in warm- and in cold-acclimated rats: the interrelation of dose of noradrenaline, its concentration in arterial plasma, and calorigenic response. Can J Physiol Pharmacol 1978; 56: 168–174.
Trayhurn P, Ashwell M, Jennings G, Richard D, Stirling DM . Effect of warm or cold exposure on GDP binding and uncoupling protein in rat brown fat. Am J Physiol 1987; 252: E237–E243.
Cancello R, Zingaretti MC, Sarzani R, Ricquier D, Cinti S . Leptin and UCP1 genes are reciprocally regulated in brown adipose tissue. Endocrinology 1998; 139: 4747–4750.
Arch JRS, Ainsworth AT, Ellis RDM, Piercy V, Thody VE, Thurlby PL et al. Treatment of obesity with thermogenic β-adrenoceptor agonists: studies on BRL 28630A in rodents. Int J Obesity 1984; 8: 1–11.
Cousin B, Castiella L, Cinti S, Champigny O, Ricquier D, Penicaud L . Atypical expression of uncoupling protein in rat adipose tissues. Int J Obesity 1992.
Himms-Hagen J, Cui J, Danforth Jr E, Taatjes DJ, Lang SS, Waters BL et al. Effect of CL-316,243, a thermogenic β3-agonist, on energy balance and brown and white adipose tissues in rats. Am J Physiol 1994; 266: R1371–R1382.
Collins S, Daniel KW, Petro AE, Surwit RS . Strain-specific response to β3-adrenergic receptor agonist treatment of diet-induced obesity in mice. Endocrinology 1997; 138: 405–413.
Champigny O, Holloway BR, Ricquier D . Regulation of UCP gene expression in brown adipocytes differentiated in primary culture. Effects of a new β-adrenoceptor agonist. Mol Cell Endocrinol 1992; 86: 73–82.
Fisher MH, Amend AM, Bach TJ, Barker JM, Brady EJ, Candelore MR et al. A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys. J Clin Invest 1998; 101: 2387–2393.
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 USA 2007; 104: 4401–4406.
Puigserver P, Wu Z, Park C, Graves R, Wright M, Spiegelman B . A cold-inducible coactivator of of nuclear receptors linked to adaptive thermogenesis. Cell 1998; 92: 829–839.
Seale P, Kajimura S, Yang W, Chin S, Rohas L, Uldry M et al. Trancriptional control of brown fat determination by PRDM16. Cell Metab 2007; 6: 38–54.
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: 961–967.
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: 1000–1004.
Kumar N, Liu D, Wang H, Robidoux J, Collins S . Orphan nuclear receptor NOR-1 enhances 3′,5′-cyclic adenosine 5′-monophosphate-dependent uncoupling protein-1 gene transcription. Mol Endocrinol 2008; 22: 1057–1064.
Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004; 431: 200–205.
Luo J, Sladek R, Carrier J, Bader JA, Richard D, Giguere V . Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Mol Cell Biol 2003; 23: 7947–7956.
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 USA 2004; 101: 8437–8442.
Kalaany NY, Gauthier KC, Zavacki AM, Mammen PP, Kitazume T, Peterson JA et al. LXRs regulate the balance between fat storage and oxidation. Cell Metab 2005; 1: 231–244.
Zhou Z, Yon Toh S, Chen Z, Guo K, Ng CP, Ponniah S et al. Cidea-deficient mice have lean phenotype and are resistant to obesity. Nat Genet 2003; 35: 49–56.
Dong B, Saha PK, Huang W, Chen W, Abu-Elheiga LA, Wakil SJ et al. Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc Natl Acad Sci USA 2009; 106: 18831–18836.
Gao J, He J, Zhai Y, Wada T, Xie W . The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J Biol Chem 2009; 284: 25984–25992.
Wang H, Zhang Y, Yehuda-Shnaidman E, Medvedev AV, Kumar N, Daniel KW et al. Liver X receptor is a transcriptional repressor of the uncoupling protein-1 gene and brown adipocyte phenotype. Mol Cell Biol 2008; 28: 2187–2200.
Bjorkhem I . Do oxysterols control cholesterol homeostasis? J Clin Invest 2002; 110: 725–730.
Russell DW . Oxysterol biosynthetic enzymes. Biochim Biophys Acta 2000; 1529: 126–135.
Chen W, Chen G, Head DL, Mangelsdorf DJ, Russell DW . Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice. Cell Metab 2007; 5: 73–79.
Seale P . Transcriptional control of brown adipocyte development and thermogenesis. Int J Obesity 2010; 34(Suppl 1): S17–S22.
Cannon B, Nedergaard J . Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue in mice (and probably in humans). Int J Obesity 2010; 34(Suppl 1): S7–S16.
Acknowledgements
We thank Dr C Nagle for providing Figure 2.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Collins, S., Yehuda-Shnaidman, E. & Wang, H. Positive and negative control of Ucp1 gene transcription and the role of β-adrenergic signaling networks. Int J Obes 34 (Suppl 1), S28–S33 (2010). https://doi.org/10.1038/ijo.2010.180
Published:
Issue Date:
DOI: https://doi.org/10.1038/ijo.2010.180
Keywords
This article is cited by
-
Acacetin alleviates energy metabolism disorder through promoting white fat browning mediated by AC-cAMP pathway
Journal of Physiology and Biochemistry (2023)
-
L-Dihydroxyphenylalanine (L-Dopa) Induces Brown-like Phenotype in 3T3-L1 White Adipocytes via Activation of Dopaminergic and β3-adrenergic Receptors
Biotechnology and Bioprocess Engineering (2022)
-
The cyclin dependent kinase inhibitor Roscovitine prevents diet-induced metabolic disruption in obese mice
Scientific Reports (2021)
-
In Situ Saturating Mutagenesis Screening Identifies a Functional Genomic Locus that Regulates Ucp1 Expression
Phenomics (2021)
-
Flavonoids as inducers of white adipose tissue browning and thermogenesis: signalling pathways and molecular triggers
Nutrition & Metabolism (2019)