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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.

Original publication

DOI

10.1038/embor.2009.177

Type

Journal article

Journal

EMBO Reports

Publication Date

10/2009

Volume

10

Pages

1175 - 1181

Addresses

Department of Physiology and Pharmacology, University of Bristol, School of Medical Sciences, University Walk, Bristol, UK.

Keywords

Hypothalamus, Animals, Mice, Rats, Glucose, Trans-Activators, Transcription Factors, Tissue Culture Techniques, Gene Expression Regulation, Cyclic AMP Response Element-Binding Protein, AMP-Activated Protein Kinases