Drosophila Cytokine Unpaired 2 Regulates Physiological Homeostasis by Remotely Controlling Insulin Secretion

SummaryIn Drosophila, the fat body (FB), a functional analog of the vertebrate adipose tissue, is the nutrient sensor that conveys the nutrient status to the insulin-producing cells (IPCs) in the fly brain to release Drosophila insulin-like peptides (Dilps). Dilp secretion in turn regulates energy balance and promotes systemic growth. We identify Unpaired 2 (Upd2), a protein with similarities to type I cytokines, as a secreted factor produced by the FB in the fed state. When upd2 function is perturbed specifically in the FB, it results in a systemic reduction in growth and alters energy metabolism. Upd2 activates JAK/STAT signaling in a population of GABAergic neurons that project onto the IPCs. This activation relieves the inhibitory tone of the GABAergic neurons on the IPCs, resulting in the secretion of Dilps. Strikingly, we find that human Leptin can rescue the upd2 mutant phenotypes, suggesting that Upd2 is the functional homolog of Leptin.

Graphical AbstractFigure optionsDownload high-quality image (224 K)Download as PowerPoint slideHighlights
► Upd2 is produced by the Drosophila fat body in response to dietary fats and sugars
► Dome activation by Upd2 in GABAergic neurons disinhibits insulin-producing cells
► This results in insulin secretion, promoting systemic growth and fat storage
► Human Leptin can signal via the Drosophila JAK/STAT receptor and substitute for Upd2