Central activation of chaperone-mediated autophagy reduces appetite by fine-tuning hypothalamic amino acid pools: new insights from fish

Chaperone-mediated Autophagy (CMA) is a key lysosomal proteolytic pathway essential for cellular homeostasis and metabolism, with dysfunction linked to various human diseases. Although extensively studied in humans and mice, CMA was only recently identified in fish, paving the way for novel and evolutionary research perspectives. Here, we demonstrate a role for CMA in regulating feed intake (FI) in rainbow trout (Oncorhynchus mykiss), a major aquaculture species and a widely used model in numerous research fields, including physiology, evolutionary genetics, toxicology, immunology, and nutrition. Specifically, we observed that feed deprivation induces an increase in the CMA activation score-a reliable proxy for CMA activity-in the hypothalamus, a central brain region involved in the regulation of feeding behavior. To probe its functional relevance, we intracerebroventricularly (ICV) injected the CMA activator CA77.1 and found a significant reduction in FI levels, suggesting a regulatory role for CMA in appetite. Further analysis suggested that CMA may regulate FI partly through changes in hypothalamic free amino acid availability, with ribosomal protein degradation potentially contributing to this mechanism. Through this mechanism, CMA may play a critical role in the precise regulation of satiety and also represent a promising target for therapeutic strategies aimed at treating metabolic disorders, as well as for nutritional interventions to improve feed efficiency and promote more sustainable growth practices in aquaculture.NEW & NOTEWORTHY This study shows in vivo, in a nonmammalian vertebrate, that chaperone-mediated Autophagy (CMA) regulates appetite. It demonstrates that hypothalamic CMA activity increases during feed deprivation and that pharmacological activation of CMA suppresses feed intake by locally modulating amino acid availability. These findings reveal a previously uncharacterized link between CMA, hypothalamic amino acid pools, and appetite regulation, and suggest a novel intracellular mechanism linking proteostasis to nutrient sensing and feeding behavior in vertebrates.

appetite; autophagy; chaperone-mediated autophagy; fish; hypothalamus.