Abstract
BackgroundThe 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.Methodology/Principal FindingsUsing 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/SignificanceThese 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.
Highlights
The hypothalamus receives information from circulating nutrients and hormones and integration of these signals by appropriate neurocircuitry will in turn translate into adaptive metabolic and behavioral responses in order to sustain energy balance
From our previous studies on COUPTFII mRNA regulation in liver and pancreas, we looked at the regulation of COUP-TFII mRNA levels in the hypothalamus of C57bl/6J adult mice according to their nutritional status
We investigated the effects of glucose and/or insulin in the control of hypothalamic COUP-TFII mRNA levels
Summary
The hypothalamus receives information from circulating nutrients and hormones and integration of these signals by appropriate neurocircuitry will in turn translate into adaptive metabolic and behavioral responses in order to sustain energy balance. Insulin secretion and peripheral glucose metabolism together with endocrine regulation are part of this integrated response Any disturbance of this mechanism leads to metabolic diseases such as obesity and diabetes [1,2]. Nuclear receptors are part of a family of ligand-activated transcription factor such as PPARs, LXRs, RXR, involved in the regulation of many key metabolic functions both at the central and peripheral level. Among these transcription factors, our team has focused its attention on the Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII named NR2F2). For the first time, a unique differential regulation of its expression by the nutritional status in the mouse hypothalamus compared to peripheral tissues
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
