title: Glucose Enhances Basal or Melanocortin-Induced cAMP-Response Element Activity in Hypothalamic Cells.
abstract: Melanocyte-stimulating hormone (MSH)-induced activation of the cAMP-response element (CRE) via the CRE-binding protein in hypothalamic cells promotes expression of TRH and thereby restricts food intake and increases energy expenditure. Glucose also induces central anorexigenic effects by acting on hypothalamic neurons, but the underlying mechanisms are not completely understood. It has been proposed that glucose activates the CRE-binding protein-regulated transcriptional coactivator 2 (CRTC-2) in hypothalamic neurons by inhibition of AMP-activated protein kinases (AMPKs), but whether glucose directly affects hypothalamic CRE activity has not yet been shown. Hence, we dissected effects of glucose on basal and MSH-induced CRE activation in terms of kinetics, affinity, and desensitization in murine, hypothalamic mHypoA-2/10-CRE cells that stably express a CRE-dependent reporter gene construct. Physiologically relevant increases in extracellular glucose enhanced basal or MSH-induced CRE-dependent gene transcription, whereas prolonged elevated glucose concentrations reduced the sensitivity of mHypoA-2/10-CRE cells towards glucose. Glucose also induced CRCT-2 translocation into the nucleus and the AMPK activator metformin decreased basal and glucose-induced CRE activity, suggesting a role for AMPK/CRTC-2 in glucose-induced CRE activation. Accordingly, small interfering RNA-induced down-regulation of CRTC-2 expression decreased glucose-induced CRE-dependent reporter activation. Of note, glucose also induced expression of TRH, suggesting that glucose might affect the hypothalamic-pituitary-thyroid axis via the regulation of hypothalamic CRE activity. These findings significantly advance our knowledge about the impact of glucose on hypothalamic signaling and suggest that TRH release might account for the central anorexigenic effects of glucose and could represent a new molecular link between hyperglycaemia and thyroid dysfunction.
authors.affiliation: Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, 80336 Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Breit
authors.affiliation: Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, 80336 Munich, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Wicht
authors.affiliation: Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, 80336 Munich, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Boekhoff
authors.affiliation: Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, 80336 Munich, Germany.
authors.forename: Evi
authors.initials: E
authors.lastname: Glas
authors.affiliation: Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, 80336 Munich, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lauffer
authors.affiliation: Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, 80336 Munich, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Mückter
authors.affiliation: Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, 80336 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C504923:Crtc2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D013973:Thyrotropin-Releasing Hormone; D009074:Melanocyte-Stimulating Hormones; D055372:AMP-Activated Protein Kinases; D005947:Glucose