Figure 7. Adipose-specific Becn1^F121A non-cell-autonomously improves systemic insulin sensitivity via promoting adiponectin secretion.

(A) WB analysis of serum adiponectin levels in Adipoq-Cre or control (WT) mice injected with AAV2/8-FLEX-Becn1^F121A and then fed with HFD for 12 weeks. n = 4. t test.

(B) ELISA of serum levels of adiponectin, resistin, and leptin in Adipoq-Cre or WT mice injected with AAV2/8-FLEX-Becn1^F121A and then fed with HFD for 12 weeks. WT+AAV-Becn1^F121A, n = 11; Adipoq-Cre+AAV-Becn1^F121A, n = 9. t test.

(C and D) Reducing adiponectin in adipose-specific Becn1^F121A mice abolishes the insulin-sensitizing effects of adipose Becn1^F121A. GTT and ITT (C) and ELISA of serum adiponectin (D) of WT and adipose-specific Becn1^F121A mice expressing both or one copy of Adiponectin after 8 weeks of HFD feeding. For GTT and ITT: WT+AAV-Becn1^F121A, n = 9; Adipoq-Cre+AAV-Becn1^F121A, n = 9; Adipoq^+/− KO+AAV-Becn1^F121A, n = 6; Adipoq^+/− KO Adipoq-Cre+AAV-Becn1^F121A, n = 5. For adiponectin ELISA: n = 5–6. One-way ANOVA with Dunnett’s test.

(E) Inhibiting early (upper), but not late (lower), stages of autophagy reduces adiponectin release to circulation in mice. WB analysis of adiponectin in the serum of HFD-fed Becn1^F121A mice treated with SBI-0206965 (SBI) or Spautin-1 (early-stage inhibitors, inhibiting autophagosome formation) or chloroquine (CQ; late-stage inhibitor, inhibiting lysosomal degradation). n = 4–6. t test.

(F) ELISA of serum adiponectin in HFD-fed Becn1^F121A mice treated with SBI-0206965, Spautin-1, or CQ. n = 5–8. One-way ANOVA with Dunnett’s test. Data represent mean ± SEM. *^,#,¶p < 0.05; **^,##,¶¶p < 0.01; ***^,###p < 0.001.

(G) Model of Becn1-regulated adiponectin secretion. When the essential autophagy protein Becn1 is released from its inhibitor Bcl-2 in adipose tissue, triggered by exercise or the active Becn1^F121A mutation, it interacts with Sec6 and other exocyst components to increase adiponectin secretion, systemic AMPK activation, and insulin sensitivity.