A Mechanism Coupling Systemic Energy Sensing to Adipokine Secretion

Area of Science:

• Cell biology
• Endocrinology
• Metabolism

Background:

• Adipocytes (fat cells) are crucial for sensing nutrients and releasing adipokines, signaling molecules that communicate systemic nutrient status.
• The precise mechanisms linking nutritional state to adipokine release remain largely unknown.
• Unpaired 2 (Upd2) in Drosophila is a functional ortholog of human leptin, a key adipokine.

Purpose of the Study:

• To investigate the mechanisms controlling the secretion of Upd2 from Drosophila fat cells.
• To identify the molecular players involved in coupling nutritional status to adipokine release.
• To explore the conserved nature of this regulatory mechanism in human leptin secretion.

Main Methods:

• Utilized Drosophila fat cells to study Unpaired 2 (Upd2) secretion.
• Investigated the role of Golgi reassembly stacking protein (GRASP) in unconventional secretion.
• Examined the impact of nutrient status, calcium (Ca2+) levels, and CaMKII phosphorylation on GRASP localization and Upd2 secretion.
• Employed a heterologous cell system to assess human leptin secretion regulation.

Main Results:

• Golgi reassembly stacking protein (GRASP) is essential for Upd2 secretion from Drosophila fat cells.
• In nutrient-rich conditions, GRASP localizes near lipid droplets (LDs).
• Nutrient deprivation increases cytosolic Ca2+ levels, which, via CaMKII, inhibits GRASP's proximity to LDs, thereby suppressing Upd2 secretion.
• Human leptin secretion is similarly regulated by Ca2+ and CaMKII.

Conclusions:

• A novel mechanism is described where increased cytosolic Ca2+ negatively regulates adipokine secretion.
• This study uncovers an evolutionarily conserved link between intracellular Ca2+ levels and energy homeostasis.
• GRASP plays a critical role in the unconventional secretion pathway of adipokines, regulated by nutrient status.