Atg8-LC3 controls systemic nutrient surplus signaling from flies to humans.

Madan, A.; Kelly, K. P.; Sullivan, C. E.; Poling, M. E.; Brent, A. E.; Alassaf, M.; Dubrulle, J.; Rajan, A.

doi:10.1101/2023.05.31.543119

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bioRxiv · 10.1101/2023.05.31.543119

Atg8-LC3 controls systemic nutrient surplus signaling from flies to humans.

Madan, A.·Kelly, K. P.·Sullivan, C. E.·Poling, M. E.·Brent, A. E.·Alassaf, M.·Dubrulle, J.·Rajan, A.

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Abstract

Organisms experience constant nutritional flux, and homeostatic mechanisms evolved to operate at the nexus of extreme nutritional states - scarcity and surplus. Thus, we surmised that decoding bidirectional molecular switches that operate at the interface of scarcity response and surplus signaling will enable the development of strategies to treat disorders that arise from nutrient imbalance states. Adipocytes secrete leptin, an interleukin protein, which signals nutrient surplus to the central brain to regulate feeding and energy expenditure. We report that Atg8-LC3-family proteins, best known for their role in autophagy, are required for leptin secretion in Drosophila and human adipocytes. Atg8-LC3 genetic knockdown and point mutations to the Atg8-LC3 interaction motif (AIM/LIR) of leptin, and its functional ortholog in Drosophila, Upd2, disrupt adipokine secretion and increase adipokine retention in human and fly cells. At an organismal level, Atg8-driven Upd2 retention increases organismal resilience to nutrient extremes by rewiring the transcriptome, organismal feeding behavior, and hunger response. Comparative proteomic analyses reveal that LC3 directs leptin to an exosome secretory pathway. We use genetic knockdown in primary human adipocytes to establish that LC3 is required for leptin secretion in a physiologically relevant mammalian system. Hence, we uncover a previously unknown and evolutionarily conserved role for Atg8-LC3 in promoting adipocyte-brain nutrient surplus signaling. We propose that Atg8-LC3s bidirectional role in nutrient sensing-conveying nutrient surplus and responding to nutrient deprivation-enables organisms to manage nutrient flux effectively.

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Madan, A., Kelly, K. P., Sullivan, C. E., Poling, M. E., Brent, A. E., Alassaf, M., Dubrulle, J., Rajan, A.. 2023-06-04. Atg8-LC3 controls systemic nutrient surplus signaling from flies to humans.. https://doi.org/10.1101/2023.05.31.543119

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