Functional interplay of distinct ATG proteins links alpha-MSH metabolism to control of food intake

Abstract

The central nervous system (CNS) is the main regulator of energy balance. In the hypothalamus, the agouti-related peptide (AgRP) neuron and the pro-opiomelanocortin (POMC) neuron that produces the anorexigenic neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) antagonistically regulate food intake and energy expenditure. Leptin receptor is highly expressed on these two neurons and leptin resistance in the CNS leads to obesity. Loss of autophagy, a cellular quality control process, in hypothalamic neurons leads to metabolic dysregulation. Loss of an essential autophagy (ATG) protein ATG7 in POMC neurons leads to obesity and glucose intolerance. The molecular mechanism of how autophagy functions in POMC neurons to regulate metabolism remains a mystery. We hypothesized that autophagy in POMC neurons responds to leptin to regulate alpha-MSH production for control of food intake and energy expenditure.;First, we investigated whether leptin activates autophagy in hypothalamic POMC neurons. We found that leptin increased levels of ATG5-ATG12, ATG16L1 and light chain 3, and increased autophagic activity. Leptin activates the upstream autophagy protein ULK1 via the Leptin receptor-b-JAK-STAT3 signaling pathway and unites these two pathways into a complex. Secondly, we studied the role of autophagy in regulating alpha-MSH levels in POMC neurons following leptin exposure. Leptin initially drives alpha-MSH production and secretion, and downregulates its lysosomal degradation. By imaging, we found that leptin increases ATG proteins at the trans-Golgi network, site of secretory vesicle synthesis, where ATG16L1-clathrin interaction is needed to form alpha-MSH-positive secretory vesicles. Blocking ATG5-ATG12 prevents delivery of these vesicles to the lysosome leading to accumulation and increased secretion of alpha-MSH. We generated a mouse model with deletion of ATG5 from POMC neurons and found that young knockout animals had reduced food intake, increased energy expenditure and reduced body weight consistent with the anorexigenic effects of alpha-MSH. We found disparate roles for ATG proteins downstream of the essential ATG7 in the production and turnover of a secretory neuropeptide. Our findings establish the first connection between leptin and autophagy in POMC neurons to regulate energy balance via fine-tuning of hypothalamic alpha-MSH levels.