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Unformatted text preview: Lack of cAMP-response Element-binding Protein 1 in the Hypothalamus Causes Obesity * S Received for publication, August 23, 2010, and in revised form, December 29, 2010 Published, JBC Papers in Press, January 5, 2011, DOI 10.1074/jbc.M110.178186 Franck Chiappini, Lucas L. Cunha, Jamie C. Harris, and Anthony N. Hollenberg 1 From the Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215 The melanocortin system in the hypothalamus controls food intake and energy expenditure. Its disruption causes severe obe- sity in mice and humans. cAMP-response element-binding pro- tein 1 (CREB1) has been postulated to play an important role downstream of the melanocortin-4 receptor (MC4R), but this hypothesis has never been confirmed in vivo . To test this, we generated mice that lack CREB1 in SIM1-expressing neurons, of the paraventricular nucleus (PVN), which are known to be MC4R-positive. Interestingly, CREB1 SIM1 mice developed obe- sity as a result of decreased energy expenditure and impairment in maintaining their core body temperature and not because of hyperphagia, defining a new role for CREB1 in the PVN. In addi- tion, the lack of CREB1 in the PVN caused a reduction in vaso- pressin expression but did not affect adrenal or thyroid func- tion. Surprisingly, MC4R function tested pharmacologically was normal in CREB1 SIM1 mice, suggesting that CREB1 is not required for intact MC4R signaling. Thus CREB1 may affect other pathways that are implicated in the regulation of body weight. The melanocortin 4 receptor (MC4R) 2 is widely expressed in the central nervous system, including a number of sites that contribute to coordinated control of body weight (13). The essential role of the MC4R is evident from the presence of severe obesity in both MC4R knock-out mice and in humans with naturally occurring mutations (4, 5). These mutations cause increased food intake and decreased energy expenditure (4, 6, 7). One key site of MC4R expression is the paraventricular nucleus of the hypothalamus (PVN) (13). The PVN is an area that regulates several neuroendocrine, behavioral, and auto- nomic functions, especially food intake and energy expenditure (811). It has been implicated in the regulation of body weight as re-expression of MC4R in the PVN of mice on a null back- ground rescues the obese phenotype (12). Mutations in the SIM1 (single-minded 1) gene, a transcription factor that con- trols development of the PVN, lead to the development of obe- sity in humans and mice, further implicating the PVN as a key regulator of body weight (1317). The MC4R is known to signal through G s , which in turn activates adenylyl cyclase, leading to increased intracellular lev- els of cAMP (1, 3, 18). Elevated cAMP levels induce phosphor- ylation and activation of the transcription factor cAMP-re- sponse element-binding protein (CREB1) through increased activity of protein kinase A, or PKA (1922). The importance ofactivity of protein kinase A, or PKA (1922)....
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