The nutritional induction of COUP-TFII gene expression in ventromedial hypothalamic neurons is mediated by the melanocortin pathway

• Published in: PloS one 2010-10, Vol.5 (10), p.e13464-e13464
• Main Authors: Sabra-Makke, Lina, Tourrel-Cuzin, Cécile, Denis, Raphaël G P, Moldes, Marthe, Pégorier, Jean-Paul, Luquet, Serge, Vasseur-Cognet, Mireille, Bossard, Pascale
• Format: Article
• Language: English
• Subjects: Albumin; Animal tissues; Animals; Anorexia; Brain; Cancer; Cell Biology/Gene Expression; Clamps; COUP Transcription Factor II - genetics; Cyclic adenosine monophosphate; Cyclic AMP; Diabetes and Endocrinology; Endocrinology; Energy balance; Energy law; Fluorescent Antibody Technique; Gene expression; Gene Expression Regulation; Genes; Genetic research; Glucose; Homeostasis; Hunger; Hypothalamus; Hypothalamus (ventromedial); Hypothalamus - metabolism; Immunofluorescence; Insulin; Life Sciences; Ligands; Melanocortin; Melanocortins - metabolism; Metabolism; Mice; Mice, Inbred C57BL; Mutation; Nervous system; Neurons; Neurons - metabolism; Nutrition/Obesity; Nutritional status; Obesity; Ovalbumin; Pancreas; Promoter Regions, Genetic; Protein expression; Proteins; Regulatory sequences; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Satiety; Signal transduction; Signaling; Sterols; Transcription activation; Transcription factors; Transcriptional Activation; Transfection; Tumorigenesis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0013464

The nuclear receptor chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) is an important coordinator of glucose homeostasis. We report, for the first time, a unique differential regulation of its expression by the nutritional status in the mouse hypothalamus compared to peripheral tissues. Using hyperinsulinemic-euglycemic clamps and insulinopenic mice, we show that insulin upregulates its expression in the hypothalamus. Immunofluorescence studies demonstrate that COUP-TFII gene expression is restricted to a subpopulation of ventromedial hypothalamic neurons expressing the melanocortin receptor. In GT1-7 hypothalamic cells, the MC4-R agonist MTII leads to a dose dependant increase of COUP-TFII gene expression secondarily to a local increase in cAMP concentrations. Transfection experiments, using a COUP-TFII promoter containing a functional cAMP responsive element, suggest a direct transcriptional activation by cAMP. Finally, we show that the fed state or intracerebroventricular injections of MTII in mice induce an increased hypothalamic COUP-TFII expression associated with a decreased hepatic and pancreatic COUP-TFII expression. These observations strongly suggest that hypothalamic COUP-TFII gene expression could be a central integrator of insulin and melanocortin signaling pathway within the ventromedial hypothalamus. COUP-TFII could play a crucial role in brain integration of circulating signal of hunger and satiety involved in energy balance regulation.