Regulation Of Energy Balance By Adenosine Receptor A₁R Expressed In The Paraventricular Nucleus Of Hypothalamus

Objective:To study 1)the effect of chronic HFD treatment on adenosine content and adenosine receptor expression in the hypothalamus;2)the role of A₁R expressed in the PVN of hypothalamus in the regulation of energy balance.Methods:We utilized a fluorometric assay to detect the adenosine contents in plasma,CSF and hypothalamus,which were collected from mice fed a chow or high-fat diet for 24 weeks.Quantitative real-time PCR and Western blot were performed to determine changes of hypothalamic expression of adenosine receptors in chow or HFD-fed mice.Expression of A₁R in the PVN was further analyzed by using immunofluorescence.We also examined the change in food intake after icv administration of adenosine or CPA,a selective A₁R agonist.Food intake,body weight and composition was monitored after lentivirus-mediated over-expression or knockdown of A₁R in the PVN.Lastly,by using immunofluorescence for c-Fos,a marker indicating neuronal activation,we examined the hypothalamic nuclei modulated by caffeine,an adenosine receptor antagonist.Results:The adenosine contents in plasma,CSF and hypothalamus are significantly elevated in HFD-fed mice.A₁R is overexpressed in the hypothalamus,especially in PVN,of HFD-fed mice as well.Food intake was evidently increased following icv administration of adenosine.In addition,we found that mice with overexpression of A₁R in the PVN neurons gained more body weights and produced less heat.These mice were hyperphagic,glucose intolerance and hypertriglyceridemic.Furthermore,lentivirus-mediated knockdown of A₁R in the PVN protected mice from HFD-induced obesity.Last but not least,we found that icv administration of caffeine increased c-Fos positive cells in the PVN,DMH and ARC of hypothalamus.Conclusions:There exists aberration of the adenosine signaling in the hypothalami of obesity mice.A₁R expressed in the PVN neurons promotes positive energy balance.