Project Details
Projekt
Defining neurocircuits in cell non-autonomous control of liver proteostasis
Applicant
Professor Dr. Jens Claus Brüning
Subject Area
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 531902955
Nutrient-dependent regulation of protein synthesis and protein quality control in liver is key to organismal metabolic homeostasis and health. It has recently been recognized that activation of ER stress in neurons can activate a systemic unfolded protein response both in C. elegans and mice. In a mouse model, expression of the constitutively active form of the transcription factor XBP1 (XBP1s) in central metabolism-regulatory proopiomelanocortin (POMC)-expressing neurons of the hypothalamus promotes cell non-autonomous activation of XBP1 in liver. We have revealed that sensory food perception in parallel promotes POMC-neuron activation as well as XBP1 mRNA splicing in liver, indicating that sensory food perception even prior to food consumption primes hepatic proteostasis for the postprandial state. Conversely, we found that fasting activates feeding promoting Agouti-related peptide (AgRP) neurons in the hypothalamus to activate autophagy in liver via activation of the hypothalamic pituitary adrenal (HPA) axis. Notably, optogenetic activation of AgRP neurons is sufficient to raise circulating corticosterone levels and to induce autophagy in liver. Conversely, blocking AgRP neuron activation abrogates fasting-induced activation of autophagy in liver. Collectively, these experiments provide a novel model for cell non-autonomous regulation of liver autophagy in adaptation to the organismal metabolic state. The current project aims at i. defining the autophagic cargo during AgRP neuron-dependent induction of liver autophagy, ii. elucidating the intracellular mechanisms in hepatocytes that underlie corticosterone-induced activation of autophagy during fasting and AgRP neuron activation and iii. defining the metabolic regulatory role of the identified autophagy pathway(s) in vivo.
DFG Programme
Research Units
