Hypothalamic Overexpression of Neurosecretory Protein GL Leads to Obesity in Mice

Abstract

Introduction: The 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. Methods: We 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. Results: Npgl 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. Conclusion: Taken 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.

Effects of Overexpression of Neurosecretory Protein GL-Precursor Gene on Glucose Homeostasis and Insulin Sensitivity in Mice

“…These data imply that NPGL affects multiple tissues, such as the intestine and WAT, to orchestrate glucose absorption and carbohydrate use for efficient de novo lipogenesis under NC conditions. In contrast to our previous study demonstrating that Npgl overexpression is unable to affect the blood glucose level in NC-fed mice [27], we again emphasize the finding that Npgl overexpression alleviated glucose intolerance, insulin resistance, and hyperglycemia in HFD-fed mice at the experimental end point of the present study. Over the past 30 years, novel molecular mechanisms linking obesity and its related disorders have been deciphered.…”

“…Hypothalamic neuropeptides predominantly control feeding behavior and metabolism and are closely linked to obesity development [ 28 , 29 ]. We recently demonstrated that hypothalamic overexpression of Npgl , a novel small secretory protein precursor gene, elicits food intake and fat accumulation in mice [ 27 ]. However, the effect of NPGL on insulin sensitivity and glucose homeostasis has not been elucidated.…”

“…Several studies have indicated that an increase in blood glucose level immediately after glucose administration can reflect glucose absorption into the circulation through the intestine [ 30 , 31 , 32 ]. In addition, our previous study has suggested that Npgl overexpression promotes the absorption of glucose, as a substrate of de novo lipogenesis, from the circulation into WAT in NC-fed mice [ 27 ]. These data imply that NPGL affects multiple tissues, such as the intestine and WAT, to orchestrate glucose absorption and carbohydrate use for efficient de novo lipogenesis under NC conditions.…”

“…ChREBP is activated and promotes de novo lipogenesis in response to carbohydrate intake, whereas dietary fat, such as polyunsaturated fatty acids, inhibits ChREBP-induced de novo lipogenesis [ 39 ]. It has been shown that Npgl overexpression upregulates mRNA expression of ChREBP in mice fed with NC and an MFSD, which include a large amount of carbohydrates [ 27 ]. Hence, we speculate that dietary carbohydrates and fat have opposite effects on NPGL action in fat accumulation, perhaps via the transcriptional factors in peripheral tissues, such as WAT.…”

“…infusion of NPGL elicits food intake and subsequent fat accumulation through de novo lipogenesis in rats [ 26 ]. Notably, overexpression of the NPGL-precursor gene ( Npgl ) in the mouse hypothalamus increases food intake and fat deposits under NC and MFSD conditions and elevates blood insulin levels without changing the blood glucose levels [ 27 ]. However, the effects of NPGL on insulin sensitivity and glucose homeostasis have not been elucidated.…”