title: CRTC3 links catecholamine signalling to energy balance.
abstract: The adipose-derived hormone leptin maintains energy balance in part through central nervous system-mediated increases in sympathetic outflow that enhance fat burning. Triggering of β-adrenergic receptors in adipocytes stimulates energy expenditure by cyclic AMP (cAMP)-dependent increases in lipolysis and fatty-acid oxidation. Although the mechanism is unclear, catecholamine signalling is thought to be disrupted in obesity, leading to the development of insulin resistance. Here we show that the cAMP response element binding (CREB) coactivator Crtc3 promotes obesity by attenuating β-adrenergic receptor signalling in adipose tissue. Crtc3 was activated in response to catecholamine signals, when it reduced adenyl cyclase activity by upregulating the expression of Rgs2, a GTPase-activating protein that also inhibits adenyl cyclase activity. As a common human CRTC3 variant with increased transcriptional activity is associated with adiposity in two distinct Mexican-American cohorts, these results suggest that adipocyte CRTC3 may play a role in the development of obesity in humans.
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Youngsup
authors.initials: Y
authors.lastname: Song
authors.forename: Judith
authors.initials: J
authors.lastname: Altarejos
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.forename: Rebecca
authors.initials: R
authors.lastname: Berdeaux
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Jason
authors.initials: J
authors.lastname: Goode
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Igata
authors.forename: Jose C
authors.initials: JC
authors.lastname: Paz
authors.forename: Meghan F
authors.initials: MF
authors.lastname: Hogan
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Singh
authors.forename: Naomi
authors.initials: N
authors.lastname: Goebel
authors.forename: Lili
authors.initials: L
authors.lastname: Vera
authors.forename: Nina
authors.initials: N
authors.lastname: Miller
authors.forename: Jinrui
authors.initials: J
authors.lastname: Cui
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Jones
authors.forename: Yii-Der I
authors.initials: YD
authors.lastname: Chen
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Willa A
authors.initials: WA
authors.lastname: Hsueh
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Marc
authors.initials: M
authors.lastname: Montminy
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001831:Body Temperature; D002395:Catecholamines / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007333:Insulin Resistance; D017058:Mexican Americans / Q000235:genetics; D051379:Mice; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D020710:RGS Proteins / Q000096:biosynthesis / Q000235:genetics; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C495791:CRTC3 protein, human; C555318:CRTC3 protein, mouse; D002395:Catecholamines; D017362:Cyclic AMP Response Element-Binding Protein; D004041:Dietary Fats; D020710:RGS Proteins; D011943:Receptors, Adrenergic, beta; C105345:Rgs2 protein, mouse; D014157:Transcription Factors; D000242:Cyclic AMP