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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.

SUBMITTER: Lerner RG

PROVIDER: S-EPMC2759732 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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A role for the CREB co-activator CRTC2 in the hypothalamic mechanisms linking glucose sensing with gene regulation.

Lerner Robin G RG Depatie Chantal C Rutter Guy A GA Screaton Robert A RA Balthasar Nina N

EMBO reports 20090828 10

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 ...[more]

PMID: 19713961

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Project description:Objective17β-Estradiol (17βE) regulates glucose homeostasis in part by centrally mediated mechanisms. In female rodents, the influence of the ovarian cycle on hypoglycemia counterregulation and glucose tolerance is unclear. We found previously that in prepubertal females, 17βE modulates glucose sensing in nonadapting glucose-inhibited (GI) and adapting GI (AdGI) neurons within the ventrolateral portion of the ventromedial nucleus (VL-VMN). Nonadapting GI neurons persistently decrease their activity as glucose increases while AdGI neurons transiently respond to a glucose increase. To begin to understand if endogenous fluctuations in estrogen levels across the estrous cycle impact hypothalamic glucose sensing and glucose homeostasis, we assessed whether hypoglycemia counterregulation and glucose tolerance differed across the phases of the estrous cycle. We hypothesized that the response to insulin-induced hypoglycemia (IIH) and/or glucose tolerance would vary throughout the estrous cycle according to changes in 17βE availability. Moreover, that these changes would correlate with estrous-dependent changes in the glucose sensitivity of VL-VMN glucose-sensing neurons (GSNs).MethodsThese hypotheses were tested in female mice by measuring the response to IIH, glucose tolerance and the glucose sensitivity of VL-VMN GSNs during each phase of the estrous cycle. Furthermore, a physiological brain concentration of 17βE seen during proestrus was acutely applied to brain slices isolated on the day of diestrous and the response to low glucose in VL-VMN GSNs was assayed.ResultsThe response to IIH was strongest during diestrous. The response of nonadapting GI and AdGI neurons to a glucose decrease from 2.5 to 0.5mM also peaked during diestrous; an effect which was blunted by the addition of 17βE. In contrast, the glucose sensitivity of the subpopulation of GSNs which are excited by glucose (GE) was not affected by estrous phase or exogenous 17βE application.ConclusionThese data suggest that physiological fluctuations in circulating 17βE levels across the estrous cycle lead to changes in hypothalamic glucose sensing and the response to IIH.

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A role for the CREB co-activator CRTC2 in the hypothalamic mechanisms linking glucose sensing with gene regulation.

Publications

A role for the CREB co-activator CRTC2 in the hypothalamic mechanisms linking glucose sensing with gene regulation.

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