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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 ?-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 ?-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.

SUBMITTER: Song Y

PROVIDER: S-EPMC3025711 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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CRTC3 links catecholamine signalling to energy balance.

Song Youngsup Y Altarejos Judith J Goodarzi Mark O MO Inoue Hiroshi H Guo Xiuqing X Berdeaux Rebecca R Kim Jeong-Ho JH Goode Jason J Igata Motoyuki M Paz Jose C JC Hogan Meghan F MF Singh Pankaj K PK Goebel Naomi N Vera Lili L Miller Nina N Cui Jinrui J Jones Michelle R MR Chen Yii-Der I YD Taylor Kent D KD Hsueh Willa A WA Rotter Jerome I JI Montminy Marc M

Nature 20101201 7326

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 c ...[more]

PMID: 21164481

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Project description:Wnt signalling and its downstream effectors are well known for their roles in embryogenesis and tumourigenesis, including the regulation of cell proliferation, survival and differentiation. In the nervous system, Wnt signalling has been described mainly during embryonic development, although accumulating evidence suggests that it also plays a major role in adult brain morphogenesis and function. Studies have predominantly concentrated on memory formation in the hippocampus, although recent data indicate that Wnt signalling is also critical for neuroendocrine control of the developed hypothalamus, a brain centre that is key in energy balance regulation and whose dysfunction is implicated in metabolic disorders such as type 2 diabetes and obesity. Based on scattered findings that report the presence of Wnt molecules in the tanycytes and ependymal cells lining the third ventricle and arcuate nucleus neurones of the hypothalamus, their potential importance in key regions of food intake and body weight regulation has been investigated in recent studies. The present review brings together current knowledge on Wnt signalling in the hypothalamus of adult animals and discusses the evidence suggesting a key role for members of the Wnt signalling family in glucose and energy balance regulation in the hypothalamus in diet-induced and genetically obese (leptin deficient) mice. Aspects of Wnt signalling in seasonal (photoperiod sensitive) rodents are also highlighted, given the recent evidence indicating that the Wnt pathway in the hypothalamus is not only regulated by diet and leptin, but also by photoperiod in seasonal animals, which is connected to natural adaptive changes in food intake and body weight. Thus, Wnt signalling appears to be critical as a modulator for normal functioning of the physiological state in the healthy adult brain, and is also crucial for normal glucose and energy homeostasis where its dysregulation can lead to a range of metabolic disorders.

Project description:Abstract CRTC3 is a member of cAMP-responsive element-binding protein (CREB)-regulated transcription coactivators (CRTCs) that plays important roles in regulating CREB-target gene expression and energy metabolism. However, there were nearly no reports about the porcine CRTC3 (pCRTC3). In the current study, we cloned the full length cDNA of pCRTC3 gene and examine its expression pattern and function in intestinal epithelial cells. The full length cDNA sequence of pCRTC3 was 2173 bp (GenBank accession no. MF964215), with a 1,860-bp open reading frame encoding a 620-AA protein. Comparison of the deduced AA sequence with different species including human, mouse, rat, papio, cattle and rabbit showed 89 to 91.9% similarity. The pCRTC3 was highly expressed in small intestine and spleen, to a lesser degree in lung, liver and adipose tissue, and was expressed at a low but detectable level in skeletal muscle, kidney and heart. In addition, high protein levels of pCRTC3 were found in IPEC-J2 cells, in which pCRTC3 was mainly localized in cytoplasm. Furthermore, we constructed pCRTC3-sgRNA1-4 expression plasmids to knockdown pCRTC3 in IPEC-J2 cells. Compared with the Lipofectamine 2000 or pX330-Cas9-empty vector control group, the expression of pCRTC3 was obviously decreased by pCRTC3-sgRNA1-4. Notably, knockdown of pCRTC3 significantly decreased the expression of the porcine tight junction related genes including ZO-1, ZO-2, Occludin, and Claudin-1 by 57.88% (P < 0.01), 40.19% (P < 0.01), 51.59% (P < 0.01) and 35.70% (P < 0.05), respectively. Meanwhile, we found oxidative stress treatment affects the expression of CRTC3 in IPEC-J2 cells.Taken together, we first cloned the full-length sequence of pCRTC3 and revealed the tissue-specific expression pattern, localization and function of pCRTC3 in regulating the expression of intestinal tight junction related genes. This study could provide some useful information for understanding the function of CRTC3 in pigs.

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CRTC3 links catecholamine signalling to energy balance.

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CRTC3 links catecholamine signalling to energy balance.

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