168-OR: Autophagy Improves Insulin Sensitivity by Regulating Adiponectin Secretion

Abstract

Autophagy is an essential lysosomal degradation pathway induced by stress. Although emerging evidence suggests that autophagy abnormality is implicated in metabolic dysfunction, the mechanism by which autophagy regulates insulin sensitivity is obscure. We recently identified a point mutation in the autophagy gene Becn1 (Becn1F121A) that leads to constitutive activation of autophagy, and generated Becn1F121A knockin mice of hyperactive autophagy. In response to high-fat diet feeding, the autophagy-hyperactive Becn1F121A mice show improved insulin sensitivity, and enhanced insulin-Akt signaling in tissues. We found that their metabolic tissues have higher activation of AMPK, which plays a central beneficial role in energy homeostasis. In addition, when added to cell culture media, serum from Becn1F121A mice can also enhance AMPK activation in the cells, suggesting a role of circulating factors in Becn1F121A-induced metabolic benefits. To further identify the autophagy-controlled circulating factor, we did a Luminex array on metabolic hormones in serum of WT and Becn1F121A mice, and detected a higher circulating level of adiponectin in Becn1F121A mice. Moreover, primary adipocytes isolated from Becn1F121A mice also secrete more adiponectin to medium, suggesting that Becn1F121A-induced adiponectin secretion is cell-autonomous. Adiponectin is an adipocyte-derived hormone that has antidiabetic effects via activating AMPK, and its blood level positively correlates with insulin sensitivity. Using biochemical approaches, we identified an interaction between Becn1 and exocyst components, and demonstrated that the Becn1F121A mutant shows higher affinity with the exocyst machinery. These data suggest that autophagy activation may improve insulin sensitivity by promoting exocyst function and adiponectin exocytosis. Our ongoing research will demonstrate for the first time how autophagy promotes adiponectin secretion, as a new mechanism by which autophagy improves metabolism. Disclosure K. Kuramoto: None. C. He: None.