title: Lack of cAMP-response element-binding protein 1 in the hypothalamus causes obesity.
abstract: The melanocortin system in the hypothalamus controls food intake and energy expenditure. Its disruption causes severe obesity in mice and humans. cAMP-response element-binding protein 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(ΔSIM1) mice developed obesity 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 addition, the lack of CREB1 in the PVN caused a reduction in vasopressin expression but did not affect adrenal or thyroid function. Surprisingly, MC4R function tested pharmacologically was normal in CREB1(ΔSIM1) 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.
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Franck
authors.initials: F
authors.lastname: Chiappini
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Lucas L
authors.initials: LL
authors.lastname: Cunha
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Harris
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215. Electronic address: thollenb@bidmc.harvard.edu.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hollenberg
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D001833:Body Temperature Regulation / Q000235:genetics; D001835:Body Weight; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism* / Q000473:pathology; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D044105:Receptor, Melanocortin, Type 4; D012097:Repressor Proteins; C492004:Creb1 protein, mouse; C101750:Sim1 protein, mouse