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Obesity is a rapidly growing health threat in modern society with only limited progress towards effective intervention.Because many environmental and behavioral factors contribute to obesity,human genetics has revealed a limited number of players for the disease.Therefore,genetic screens in mice in laboratory setting offer advantages to identify novel genetic determinants and potential therapeutic targets for obesity.We have screened mouse mutants generated by piggyBacinsertional mutagenesis during the past several years.Here we reported six novel loci as the result of a pilot screen of 408 mutants.In particular,we described the role of GPRx,an orphan G protein-coupled receptor(GPCR)in obesity.Disruption of GPRx leads to morbid obesity before weaning,followed by glucose intolerance and hepatic steatosis with advancing age.Reduced expression of the metabolic regulator POMC and less energy expenditure were observed prior to obesity.We provide evidence suggesting that GPRx regulates POMC expression via the JAK/STAT pathway,in a cell autonomous manner.Consistently,intraventricular administration of MTII,an analog of POMC derivative α-MSH,suppressed adult obesity in GPRx mutants.These results not only uncovers a novel regulator of POMC and energy expenditure,but also offers a new candidate target for fighting against obesity.