A Mechanism Coupling Systemic Energy Sensing to Adipokine Secretion

Publication date: 9 October 2017
Source:Developmental Cell, Volume 43, Issue 1
Author(s): Akhila Rajan, Benjamin E. Housden, Frederik Wirtz-Peitz, Laura Holderbaum, Norbert Perrimon
Adipocytes sense systemic nutrient status and systemically communicate this information by releasing adipokines. The mechanisms that 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 Golgi reassembly stacking protein (GRASP), an unconventional secretion pathway component, is required for Upd2 secretion. In nutrient-rich fat cells, GRASP clusters in close proximity to the 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.

Graphical abstract

Teaser

Rajan et al. identify a mechanism coupling nutrient status to adipocyte-mediated adipokine secretion involving glucagon-mediated calcium signaling and GRASP, an unconventional secretion protein. In fly fat cells, leptin ortholog Upd2 is associated with GRASP near lipid droplets, and, upon nutrient deprivation, increased calcium levels negatively regulate adipokine secretion via GRASP.


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