A Mechanism Coupling Systemic Energy Sensing to Adipokine Secretion

Abstract

Adipocytes sense systemic nutrient status and systemically communicate this information by releasing adipokines. The mechanisms which couple nutritional state to adipokine release are unknown. Here, we investigated how Unpaired 2 (Upd2), a structural and functional ortholog of the primary human adipokine Leptin, is released from Drosophila fat cells. We find that GRASP, an unconventional secretion pathway component, is required for Upd2 secretion. In nutrient rich fat cells, GRASP clusters in close proximity to apical side of lipid droplets (LDs). During nutrient deprivation, Glucagon mediated increase in Calcium (Ca2+) levels, via Calmodulin kinase II (CaMKII) phosphorylation, inhibits proximal GRASP localization to LDs. Using a heterologous cell system, we show that human Leptin secretion is also regulated by Ca2+ and CaMKII. In summary, we describe a mechanism by which increased cytosolic Ca2+ negatively regulates adipokine secretion and have uncovered an evolutionarily conserved molecular link between intracellular Ca2+ levels and energy homeostasis.