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


RESULTS
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.


CONCLUSIONS
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.
Sabra-Makke
Lina
L
Institut Cochin, Université Paris Descartes, Department of Endocrinology, Metabolism and Cancer, CNRS (UMR 8104), Paris, France.
Tourrel-Cuzin
Cécile
C
Denis
Raphaël G P
RG
Moldes
Marthe
M
Pégorier
Jean-Paul
JP
Luquet
Serge
S
Vasseur-Cognet
Mireille
M
Bossard
Pascale
P
D000818:Animals; D051837:COUP Transcription Factor II / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D007031:Hypothalamus / Q000378:metabolism*; D053486:Melanocortins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation
D051837:COUP Transcription Factor II; D053486:Melanocortins; C497587:Nr2f2 protein, mouse