Hypothalamic Overexpression of Neurosecretory Protein GL Leads to Obesity in Mice

Abstract

IntroductionThe mechanisms underlying obesity are not fully understood, necessitating the creation of novel animal models for investigation of metabolic disorders from the cellular-molecular to behavioral levels of analysis. We have previously found that neurosecretory protein GL (NPGL), a newly-identified hypothalamic neuropeptide, is involved in feeding behavior and fat accumulation in rats. Given the broad availability of genetic tools in mice, the present investigation sought to establish a mouse model of NPGL-induced obesity. MethodsWe overexpressed the NPGL-precursor gene (Npgl) in the hypothalamus using adeno-associated virus in C57BL/6J mice fed normal chow (NC) or a high-calorie diet (HCD). After 9 weeks of Npgl overexpression, we measured adipose tissues, muscle, and several organ masses in addition to food intake and body mass. To assess the effects of Npgl overexpression on peripheral tissues, we analyzed mRNA expression of lipid metabolism-related genes by quantitative RT-PCR. ResultsNpgl overexpression increased food intake, body mass, adipose tissues and liver masses, food efficiency, and circulating insulin levels under both NC and HCD, resulting in obesity observable within 8 weeks. Furthermore, we observed fat accumulation in adipose tissues and liver. Additionally, mRNA expression of lipid metabolism-related factors was increased in white adipose tissue and the liver after Npgl overexpression. ConclusionTaken together, the present study suggests that NPGL is an endogenous obesogenic factor that acts within a short period of time in mice. As a result, this animal model can be widely applied to study the etiology of obesity from genes to behavior.