Decoding the link between metabolism and endocytic trafficking

• Applicant: Professorin Anja Zeigerer, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568814450

Endocytic trafficking has recently emerged as critical for maintaining metabolic homeostasis. It is responsible for the sorting and distributing of signalling receptors, membrane transporters, hormones, and other ligands between the plasma membrane and different intracellular compartments. In the liver, hepatocytes sense nutritional cues and promptly integrate this information intracellularly. This is especially important during the fasting-feeding transition, where glucose and lipid metabolism must be tightly regulated. In response to fasting, the liver upregulates glucagon-driven processes; in response to feeding, it upregulates insulin-driven processes. Hepatic endosomes make these fast responses possible by regulating the plasma membrane proteome and downstream signalling within minutes of food intake. However, which molecular mechanisms underlie the endosomal responses to nutritional cues remains unclear. We and others have recently identified several endo-lysosomal proteins, including Rab5, Rab24, and Vps37a, as key metabolic signalling regulators. Our preliminary data indicate that fasting/feeding cues induce a spatial and temporal re-organization of the liver's endo-lysosomal system. Specific phosphoinositide kinases and phosphatases localize to endosomes and recruit recycling complexes; this, in turn, increases the transport of metabolic transporters and receptors to the plasma membrane for use during refeeding. Here, we propose to dissect the responsible signals and underlying molecular mechanisms. In particular, we plan to investigate 1) physiological endo-lysosomal changes during the fasting-feeding transition in the liver, 2) hormonal and nutritional cues that regulate the formation of phosphoinositides as anchors for their membrane redistribution, and 3) the most prominent recycling complex, Retromer, in fasting and refeeding as well as in metabolic liver diseases. We will use in vivo mouse models and primary polarized mouse hepatocytes to analyse proteomic and metabolomic changes using physiological, biochemical, cell biological, and computational methods. As this project is at an exciting new interface between liver metabolism and endocytic trafficking, our comprehensive, multidisciplinary approach has the potential to identify novel mechanisms and players involved in the physiological responses to fasting and feeding.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Dr. Jerome Gilleron