title: A role for the CREB co-activator CRTC2 in the hypothalamic mechanisms linking glucose sensing with gene regulation.
abstract: Within the central nervous system (CNS), the hypothalamus senses and integrates information on the nutrient state of the body. However, the molecular mechanisms translating nutrient sensing into changes in gene expression and, ultimately, nutrient intake remain unclear. A crucial function for the cyclic AMP-response element binding protein (CREB) co-activator CREB-regulated transcription co-activator 2 (CRTC2) in maintaining glucose homeostasis has been shown in the liver. Here, we report CRTC2 expression in distinct areas of the CNS, including hypothalamic neurons. We show that hypothalamic CRTC2 phosphorylation and subcellular localization is altered by nutrient state. Specifically, glucose regulates hypothalamic CRTC2 activity via AMP-activated protein kinase (AMPK)-mediated phosphorylation of CRTC2. Hypothalamic AMPK controls the expression of the cAMP response element (CRE) gene, insulin receptor substrate 2 (Irs2), by regulating CRTC2 occupancy of the Irs2 promoter. Indeed, CRTC2 is required for the appropriate expression of specific hypothalamic CRE genes. Our data identify CRTC2 as a new hypothalamic AMPK target and highlight a role for CRTC2 in the mechanisms linking hypothalamic glucose sensing with CRE gene regulation.
authors.affiliation: Department of Physiology and Pharmacology, University of Bristol, School of Medical Sciences, University Walk, Bristol, UK.
authors.forename: Robin G
authors.initials: RG
authors.lastname: Lerner
authors.forename: Chantal
authors.initials: C
authors.lastname: Depatie
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.forename: Robert A
authors.initials: RA
authors.lastname: Screaton
authors.forename: Nina
authors.initials: N
authors.lastname: Balthasar
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D051379:Mice; D051381:Rats; D046509:Tissue Culture Techniques; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: C545700:CRTC2 protein, rat; C504923:Crtc2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D015534:Trans-Activators; D014157:Transcription Factors; D055372:AMP-Activated Protein Kinases; D005947:Glucose