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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.

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Figure 1: Crtc3 −/− mice are resistant to obesity.
Figure 2: Increased energy expenditure in Crtc3 −/− mice.
Figure 3: Increased catecholamine signalling in Crtc3 −/− adipose tissue.
Figure 4: Crtc3 attenuates adipose tissue cAMP signalling.

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Acknowledgements

This study was supported in part by National Institutes of Health grants R01-DK049777, R01-DK083834, P30-DK063491, R01-HL088457, R01-DK79888, R01-HL071205, N01-HC95159, N02-HL64278and M01-RR00425 (General Clinical Research Center Grant from the National Center for Research Resources, The J.W. Kieckhefer Foundation, The Clayton Medical Research Foundation, Inc., The Helmsley Foundation, the Cedars-Sinai Winnick Clinical Scholars Award (to M.O.G.) and the Cedars-Sinai Board of Governor’s Chair in Medical Genetics (J.I.R.). We thank B. Beutler and O. Siggs (The Scripps Research Institute) for help with macrophage studies.

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Y.S., J.A. and M.M. conceived the project and experimental design. M.O.G. analysed human data. Y.S., J.A., H.I., R.B., J.K., J.G., M.I., J.P., M.F.H., P.K.S., N.G., L.V. and N.M. performed experiments and data analysis. X.G. designed and supervised human data analysis. J.C. performed statistical analysis. M.R.G. performed genotyping experiments. Y.-D.I.C. was involved in study design. K.D.T. designed and supervised human genotyping experiments. W.A.H. and J.I.R. designed and conceived the MACAD study. Y.S., M.O.G. and M.M. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Marc Montminy.

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Song, Y., Altarejos, J., Goodarzi, M. et al. CRTC3 links catecholamine signalling to energy balance. Nature 468, 933–939 (2010). https://doi.org/10.1038/nature09564

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