Atg8/LC3 controls systemic nutrient surplus signaling in flies and humans

Area of Science:

• Cell Biology
• Metabolic Regulation
• Molecular Mechanisms

Background:

• Organisms must maintain energy homeostasis amidst fluctuating nutrient availability.
• Adipocytes secrete adipokines like leptin to signal nutrient status, but mechanisms of leptin secretion from human cells are unclear.
• Obesity involves metabolic dysregulation linked to altered leptin secretion.

Purpose of the Study:

• To investigate the role of Atg8/LC3 proteins in adipokine secretion from human adipocytes.
• To elucidate the molecular mechanisms governing leptin release under nutrient surplus conditions.
• To understand the bidirectional function of Atg8/LC3 in nutrient sensing.

Main Methods:

• Studied Atg8/LC3 family proteins in human adipocytes and Drosophila models.
• Utilized proteomic analysis to identify protein interactions and pathways.
• Investigated extracellular vesicle (EV) mediated secretion pathways.

Main Results:

• Atg8/LC3 proteins promote the secretion of leptin and its Drosophila ortholog, unpaired 2 (Upd2), during nutrient surplus.
• LC3 directs leptin to a specific secretory pathway involving LC3-dependent extracellular vesicle loading and secretion (LDELS).
• Mutations affecting Atg8 interaction with Upd2 in Drosophila lead to adipokine retention, altered lipid storage, hunger response, and transcriptome changes.

Conclusions:

• Atg8/LC3 proteins play a conserved, bidirectional role in nutrient sensing, facilitating adipokine secretion during surplus and responding to deprivation.
• LDELS represents a novel secretory route for leptin in human adipocytes.
• Understanding Atg8/LC3's function offers potential therapeutic targets for metabolic disorders.