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Dev Cell. 2017 Oct 9;43(1):83-98.e6. doi: 10.1016/j.devcel.2017.09.007.

A Mechanism Coupling Systemic Energy Sensing to Adipokine Secretion.

Author information

1
Basic Sciences Division, Fred Hutch, Seattle, WA 98109, USA. Electronic address: akhila@fredhutch.org.
2
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
3
Basic Sciences Division, Fred Hutch, Seattle, WA 98109, USA.
4
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: perrimon@genetics.med.harvard.edu.

Abstract

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.

KEYWORDS:

CaMKII; Upd2; adipocyte; calcium; fat; glucagon; homeostasis; insulin; leptin; unconventional secretion

PMID:
29017032
PMCID:
PMC5650192
DOI:
10.1016/j.devcel.2017.09.007
[Indexed for MEDLINE]
Free PMC Article

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