Autophagy is a lysosomal degradation pathway that plays pivotal roles in maintaining cellular homeostasis. Beclin1/BECN1 is a key autophagy protein that regulates the stability and kinase activity of the class III phosphatidylinositol 3-kinase complex. Dysregulation of autophagy results in the pathogenesis of a variety of diseases, including type 2 diabetes. However, the molecular mechanism of the autophagy machinery in metabolic regulation is poorly understood. To elucidate how autophagy and BECN1 are involved in energy homeostasis and insulin sensitivity, we generated a unique knock-in mouse model showing hyperactive autophagy. This mouse model carries a single amino acid substitution (F121A) in the BECN1 protein (BECN1F121A), which disrupts an inhibitory binding between BECN1 and BCL2, leading to constitutive activation of autophagy. Using this moue model, we discovered that in addition to a role in autophagic regulation, BECN1 also executes a non-degradative function. We found that in response to high-fat diet feeding, BECN1F121A mice show improved systemic insulin sensitivity, elevated adiponectin levels in the circulation, and enhanced adiponectin signaling in metabolic tissues, compared to wild type (WT) mice, despite that body weight and white adipose tissue weight are similar between the two genotypes. Using adipocyte-differentiated stromal vascular fraction cells, we further found that compared to WT BECN1, the BECN1F121A mutant interacts more strongly with components of the exocyst, a complex required for secretory vesicle docking at the plasma membrane. Finally, we demonstrated that the BECN1-exocyst interaction is mechanistically mediated through the coiled-coil domain of BECN1. Altogether, our findings suggest that BECN1 regulates adiponectin secretion through interacting with the exocyst in white adipose tissues, and highlight that autophagy proteins may play important non-degradative roles in energy metabolism.
K. Kuramoto: None. C. He: None.