CCK Response Deficiency in Synphilin-1 Transgenic Mice.

Wanli W Smith,Tianxia Li,Megan Smith,Dejun Yang,Alexander Moghadam,Timothy H Moran,François Blachier,Pique P Choi

doi:10.1371/journal.pone.0142314

Wanli W Smith, Tianxia Li + Show 6 more

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https://doi.org/10.1371/journal.pone.0142314

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Abstract

Previously, we have identified a novel role for the cytoplasmic protein, synphilin-1(SP1), in the controls of food intake and body weight in both mice and Drosophila. Ubiquitous overexpression of human SP1 in brain neurons in transgenic mice results in hyperphagia expressed as an increase in meal size. However, the mechanisms underlying this action of SP1 remain to be determined. Here we investigate a potential role for altered gut feedback signaling in the effects of SP1 on food intake. We examined responses to peripheral administration of cholecytokinin (CCK), amylin, and the glucagon like peptide-1 (GLP-1) receptor agonist, exendin-4. Intraperitoneal administration of CCK at doses ranging from 1–10 nmol/kg significantly reduced glucose intake in wild type (WT) mice, but failed to affect intake in SP1 transgenic mice. Moreover, there was a significant attenuation of CCK-induced c-Fos expression in the dorsal vagal complex in SP1 transgenic mice. In contrast, WT and SP1 transgenic mice were similarly responsive to both amylin and exendin-4 treatment. These studies demonstrate that SP1 results in a CCK response deficiency that may contribute to the increased meal size and overall hyperphagia in synphillin-1 transgenic mice.

Highlights

Obesity is the most common metabolic disease and its worldwide prevalence makes obesity a major health problem
The major finding of this study is that SP1 mice are deficient in their response to exogenous CCK both in terms of the effect on food intake and hindbrain neural activation
Our previous studies demonstrate that hyperphagia in SP1 mice results in obesity since SP1 mice are pair-fed with the same amount of food as wild type (WT) mice for 10 weeks, which can totally prevent the SP1-induced obesity [1]

Summary

Introduction

Obesity is the most common metabolic disease and its worldwide prevalence makes obesity a major health problem. The pathogenesis of obesity remains incompletely understood. We have identified a novel role for SP1 in the control of food intake and body weight in transgenic mice and flies [1,2,3,4]. Ubiquitous overexpression of SP1 in brain neurons results in hyperphagia and obesity in both mice and Drosophila. SP1, a 919 amino acid protein, was first identified as an alpha-synuclein interacting protein by yeast two hybrid analysis [5]. We and others have demonstrated that SP1 associates with alpha-synuclein promoting the formation of intracellular inclusions, and plays a protective role against neuronal toxicity in Parkinson’s disease cell and mouse models [5,6,7,8,9,10]. Our recent studies have shown that SP1 binds ATP and GTP, and increases cellular

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