Highlights d Mfn2 binds directly and specifically to phosphatidylserine (PS) d Hepatic Mfn2 deficiency causes a reduced transfer of PS from ER to mitochondria d Mfn2 ablation in liver causes a NASH-like phenotype and liver cancer d A defective transfer of PS from ER to mitochondria causes liver disease

We generated mice that overexpress protein targeting to glycogen (PTG) in the liver (PTG OE ), which results in an increase in liver glycogen. When fed a high-fat diet (HFD), these animals reduced their food intake. The resulting effect was a lower body weight, decreased fat mass, and reduced leptin levels. Furthermore, PTG overexpression reversed the glucose intolerance and hyperinsulinemia caused by the HFD and protected against HFD-induced hepatic steatosis. Of note, when fed an HFD, PTG OE mice did not show the decrease in hepatic ATP content observed in control animals and had lower expression of neuropeptide Y and higher expression of proopiomelanocortin in the hypothalamus. Additionally, after an overnight fast, PTG OE animals presented high liver glycogen content, lower liver triacylglycerol content, and lower serum concentrations of fatty acids and b-hydroxybutyrate than control mice, regardless of whether they were fed an HFD or a standard diet. In conclusion, liver glycogen accumulation caused a reduced food intake, protected against the deleterious effects of an HFD, and diminished the metabolic impact of fasting. Therefore, we propose that hepatic glycogen content be considered a potential target for the pharmacological manipulation of diabetes and obesity.Liver glycogen acts as an energy store in times of nutritional sufficiency for use in times of need. The metabolism of this polysaccharide in the liver is controlled by the activities of two key enzymes: glycogen synthase (GS) and glycogen phosphorylase (GP) (1). GS is phosphorylated at multiple sites, which induces its inactivation, whereas GP is activated by phosphorylation at a single site. Both enzymes are also regulated allosterically (2,3).Glycogen-targeting subunits bind to glycogen and protein phosphatase 1 (PP1) and facilitate the dephosphorylation of GS and GP, thus activating the former and inactivating the latter. Six genes encode glycogen-targeting subunits (4). Among these, protein targeting to glycogen (PTG) (PPP1R3C or PPP1R5), which is expressed in many tissues, has been shown to control glycogen stores in various animal models (5-7).Adenoviral PTG overexpression in the liver of normal rats increases glycogen and improves glucose tolerance without perturbing lipid metabolism (8). In a diabeticfocused approach, Yang and Newgard (9) showed that adenoviral expression of PTG in the liver of STZ-diabetic rats increased glycogen content and reversed hyperglycemia and hyperphagia. Through a different approach, we reported that hepatic adenoviral expression of an active form of liver GS (LGS), which also increases glycogen content, in STZ-diabetic rats reduced food intake and hyperglycemia (10).Russek (11) was the first to propose a hepatostatic theory of food intake, which was further redefined as a glycogenostatic model by Flatt (12). This model predicts that individuals consume food to a level that maintains glycogen levels in the body (12). In fact, many lines of experimental evidence establish a correlation between the size of liver ...

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Neuregulin (NRG) is an EGF-related growth factor that binds to the tyrosine kinase receptors ErbB3 and ErbB4, thus inducing tissue development and muscle glucose utilization during contraction. Here, we analyzed whether NRG has systemic effects regulating glycemia in control and type 2 diabetic rats. To this end, recombinant NRG (rNRG) was injected into Zucker diabetic fatty (ZDF) rats and their respective lean littermates 15 min before a glucose tolerance test (GTT) was performed. rNRG enhanced glucose tolerance without promoting the activation of the insulin receptor (IR) or insulin receptor substrates (IRS) in muscle and liver. However, in control rats, rNRG induced the phosphorylation of protein kinase B (PKB) and glycogen synthase kinase-3 (GSK-3) in liver but not in muscle. In liver, rNRG increased ErbB3 tyrosine phosphorylation and its binding to phosphatidylinositol 3-kinase (PI3K), thus indicating that rNRG activates the ErbB3/PI3K/PKB signaling pathway. rNRG increased glycogen content in liver but not in muscle. rNRG also increased the content of fructose-2,6-bisphosphate (Fru-2,6-P2), an activator of hepatic glycolysis, and lactate in liver but not in muscle. Increases in lactate were abrogated by wortmannin, a PI3K inhibitor, in incubated hepatocytes. The liver of ZDF rats showed a reduced content of ErbB3 receptors, entailing a minor stimulation of the rNRG-induced PKB/GSK-3 cascade and resulting in unaltered hepatic glycogen content. Nonetheless, rNRG increased hepatic Fru-2,6-P2 and augmented lactate both in liver and in plasma of diabetic rats. As a whole, rNRG improved response to the GTT in both control and diabetic rats by enhancing hepatic glucose utilization.

Glycogen shortage during fasting coincides with dramatic changes in hepatic adenine nucleotide levels. The aim of this work was to study the relevance of liver glycogen in the regulation of the hepatic energy state during food deprivation. To this end, we examined the response of mice with sustained increased liver glycogen content to prolonged fasting. In order to increase hepatic glycogen content, we generated mice that overexpress protein targeting to glycogen (PTG) in the liver (PTG OE mice). Control and PTG OE mice were fed ad libitum or fasted for 36 h. Upon fasting, PTG OE mice retained significant hepatic glycogen stores and maintained hepatic energy status. Furthermore, we show that liver glycogen controls insulin sensitivity, gluconeogenesis, lipid metabolism, and ketogenesis upon nutrient deprivation.