CRTC3 links catecholamine signalling to energy balance

The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature (Impact Factor: 41.46). 12/2010; 468(7326):933-9. DOI: 10.1038/nature09564
Source: PubMed


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.

Download full-text


Available from: Jerome I Rotter,
  • Source
    • "The CNVs that include the CRTC3 gene have higher copy number in dogs (with the exception of the dingo) than in gray wolves. It has been shown that CRTC3−/−m ice maintained on a normal chow diet appear more insulin-sensitive than controls and also have 50% lower adipose tissue mass than control mice despite comparable physical activity [33]. Incidence of overweight and obesity in dogs exceeds 30%, and several breeds are predisposed to this heritable phenotype [34]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Although a variety of genetic changes have been implicated in causing phenotypic differences among dogs, the role of copy number variants (CNVs) and their impact on phenotypic variation is still poorly understood. Further, very limited knowledge exists on structural variation in the gray wolf, the ancestor of the dog, or other closely related wild canids. Documenting CNVs variation in wild canids is essential to identify ancestral states and variation that may have appeared after domestication. Results In this work, we genotyped 1,611 dog CNVs in 23 wolf-like canids (4 purebred dogs, one dingo, 15 gray wolves, one red wolf, one coyote and one golden jackal) to identify CNVs that may have arisen after domestication. We have found an increase in GC-rich regions close to the breakpoints and around 1 kb away from them suggesting that some common motifs might be associated with the formation of CNVs. Among the CNV regions that showed the largest differentiation between dogs and wild canids we found 12 genes, nine of which are related to two known functions associated with dog domestication; growth (PDE4D, CRTC3 and NEB) and neurological function (PDE4D, EML5, ZNF500, SLC6A11, ELAVL2, RGS7 and CTSB). Conclusions Our results provide insight into the evolution of structural variation in canines, where recombination is not regulated by PRDM9 due to the inactivation of this gene. We also identified genes within the most differentiated CNV regions between dogs and wolves, which could reflect selection during the domestication process. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-465) contains supplementary material, which is available to authorized users.
    BMC Genomics 06/2014; 15(1):465. DOI:10.1186/1471-2164-15-465 · 3.99 Impact Factor
  • Source
    • "RGS2 acts as an attenuator of signal transduction for GPCRs via enhancement of the rate of GTP hydrolysis by Gαi [18], [19] which couples negatively to ACs. RGS2 has also been shown to interact directly with AC3 and AC5 to inhibit the synthesis of cAMP [20], [21], [39]. Importantly, cAMP signaling has been a proposed deficit in HD brain [40], [41], and AC5 is the prominent AC in striatum, the most affected HD brain region. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The molecular phenotype of Huntington's disease (HD) is known to comprise highly reproducible changes in gene expression involving striatal signaling genes. Here we test whether individual changes in striatal gene expression are capable of mitigating HD-related neurotoxicity. We used protein-encoding and shRNA-expressing lentiviral vectors to evaluate the effects of RGS2, RASD2, STEP and NNAT downregulation in HD. Of these four genes, only RGS2 and RASD2 modified mutant htt fragment toxicity in cultured rat primary striatal neurons. In both cases, disease modulation was in the opposite of the predicted direction: whereas decreased expression of RGS2 and RASD2 was associated with the HD condition, restoring expression enhanced degeneration of striatal cells. Conversely, silencing of RGS2 or RASD2 enhanced disease-related changes in gene expression and resulted in significant neuroprotection. These results indicate that RGS2 and RASD2 downregulation comprises a compensatory response that allows neurons to better tolerate huntingtin toxicity. Assessment of the possible mechanism of RGS2-mediated neuroprotection showed that RGS2 downregulation enhanced ERK activation. These results establish a novel link between the inhibition of RGS2 and neuroprotective modulation of ERK activity. Our findings both identify RGS2 downregulation as a novel compensatory response in HD neurons and suggest that RGS2 inhibition might be considered as an innovative target for neuroprotective drug development.
    PLoS ONE 07/2011; 6(7):e22231. DOI:10.1371/journal.pone.0022231 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In fasting mammals, the liver is the primary source of glucose production for maintenance of normoglycemia. In this setting, circulating peptide hormones and catecholamines cause hepatic glucose output by stimulating glycogen breakdown as well as de novo glucose production through gluconeogenesis. Fasting gluconeogenesis is regulated by a complex transcriptional cascade culminating in elevated expression of hepatic enzymes that promote gluconeogenesis and glucose export to the blood. The cAMP response element binding protein CREB and its co-activator CRTC2 play crucial roles in signal-dependent transcriptional regulation of gluconeogenesis. Recent work has identified a family of serine/threonine kinases, the salt inducible kinases (SIKs), which are subject to hormonal control and constrain gluconeogenic and lipogenic gene expression in liver. As normal regulation of gluconeogenesis and lipogenesis is disrupted in diabetic states, SIK kinases are poised to serve as therapeutic targets to modulate metabolic disturbances in diabetic patients. The purpose of this review is to 1) describe the identification of CRTCs CREB co-activators and their regulation by SIKs, 2) discuss recent progress toward understanding regulation and function of SIKs in metabolism and 3) examine the potential clinical impact of therapeutics that target SIK kinase function. Keywordssalt inducible kinases (SIKs)–cAMP response element binding protein (CREB)–CRTC–gluconeogenesis–lipogenesis–type 2 diabetes–transcription
    01/2011; 6(3):231-241. DOI:10.1007/s11515-011-1148-0
Show more