Effects of hepatic glycogen on food intake and glucose homeostasis are mediated by the vagus nerve in mice

Liver glycogen plays a key role in regulating food intake and blood glucose. Mice that accumulate large amounts of this polysaccharide in the liver are protected from high-fat diet (HFD)-induced obesity by reduced food intake. Furthermore, these animals show reversal of the glucose intolerance and hyperinsulinaemia caused by the HFD. The aim of this study was to examine the involvement of the hepatic branch of the vagus nerve in regulating food intake and glucose homeostasis in this model. We performed hepatic branch vagotomy (HBV) or a sham operation on mice overexpressing protein targeting to glycogen (Ptg (OE)). Starting 1 week after surgery, mice were fed an HFD for 10 weeks. HBV did not alter liver glycogen or ATP levels, thereby indicating that this procedure does not interfere with hepatic energy balance. However, HBV reversed the effect of glycogen accumulation on food intake. In wild-type mice, HBV led to a significant reduction in body weight without a change in food intake. Consistent with their body weight reduction, these animals had decreased fat deposition, adipocyte size, and insulin and leptin levels, together with increased energy expenditure. Ptg (OE) mice showed an increase in energy expenditure and glucose oxidation, and these differences were abolished by HBV. Moreover, Ptg (OE) mice showed an improvement in HFD-induced glucose intolerance, which was suppressed by HBV. Our results demonstrate that the regulation of food intake and glucose homeostasis by liver glycogen is dependent on the hepatic branch of the vagus nerve.