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.
Institut Cochin, Université Paris Descartes, Department of Endocrinology, Metabolism and Cancer, CNRS (UMR 8104), Paris, France.
Lina
L
Sabra-Makke
Cécile
C
Tourrel-Cuzin
Raphaël G P
RG
Denis
Marthe
M
Moldes
Jean-Paul
JP
Pégorier
Serge
S
Luquet
Mireille
M
Vasseur-Cognet
Pascale
P
Bossard
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