Uncovering the reciprocal relationship between endocytosis and metabolism during the fasting-feeding transition in the liver

• Applicant: Professorin Dr. Anja Zeigerer, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Public Health, Healthcare Research, Social and Occupational Medicine ; Cell Biology
• Term: from 2014 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264299965

The global prevalence of obesity and type-2 diabetes, has reached a qualified epidemic stage. This presents a heavy burden on our society and thus, it is essential to fight metabolic abnormalities such as type-2 diabetes. Type-2 diabetes is the consequences of multi-organ deficiencies resulting in a mis-regulation of glucose homeostasis. The liver is a main organ controlling whole body glucose homeostasis, which is particularly evident during the fasting/feeding transition, where hepatocytes sense external nutrient availabilities and consequently respond by adjusting glucose production and storage. So far, research has mainly focused on understanding the molecular pathways controlling the fasting/feeding transition, however, the underlying intracellular remodeling processes contributing to the adapted hepatocellular metabolic response are not well understood. Recently, we and others have highlighted for the first time the endocytic system as a new cellular module involved in the regulation of glucose metabolism. Knockdown of the endosomal GTPase Rab5 in mouse liver led to an inhibition of liver glucose production. More recently, our preliminary results discovered a collective responsiveness of the endosomal system to feeding cues in the liver, suggesting a potential differential function of endosomal trafficking during the fasted and fed state. In particular, we identified Vps37a, a component of the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery, which is necessary for receptor downregulation, to have a regulatory function on insulin-induced AKT phosphorylation and gluconeogenic gene expression. Interestingly, we found Vps37a to be downregulated in db/db mice and in diabetic patients with fatty liver disease, indicative of its translational potential.Consequently, the present proposal aims at understanding the molecular mechanism, by which Vps37a regulates insulin signaling and glucose metabolism in the liver. Using overexpression and knockdown techniques, we plan to dissect the novel function of this ESCRT component on glucose homeostasis in primary mouse and human hepatocytes in vitro and in control and diabetic mouse models in vivo. In addition, we will further characterize the reorganization of the endosomal system during fasting and re-feeding and aim to unravel the physiological underlying mechanism that highlights the contribution of the endocytic network in mediating the fasting/feeding transition. We will particularly focus on ubiquitination as a signal for receptor and cargo downregulation during the fasting/feeding switch. Altogether, this project is anticipated to provide novel insights into the intracellular regulation of glucose metabolism during the fasting/feeding transition via involvement of membrane transport processes in the liver and pave the way for their exploitation in the control of hepatic glucose production and thus the treatment of type-2 diabetes.

• DFG Programme: Research Grants