Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Cell Rep. 2021 May 25;35(8):109184. doi: 10.1016/j.celrep.2021.109184.
Autophagy dysregulation is implicated in metabolic diseases, including type 2 diabetes. However, the mechanism by which the autophagy machinery regulates metabolism is largely unknown. Autophagy is generally considered a degradation process via lysosomes. Here, we unveil a metabolically important non-cell-autonomous, non-degradative mechanism regulated by the essential autophagy protein Becn1 in adipose tissue. Upon high-fat diet challenge, autophagy-hyperactive Becn1 mice show systemically improved insulin sensitivity and enhanced activation of AMP-activated protein kinase (AMPK), a central regulator of energy homeostasis, via a non-cell-autonomous mechanism mediated by adiponectin, an adipose-derived metabolic hormone. Adipose-specific Becn1 expression is sufficient to activate AMPK in non-adipose tissues and improve systemic insulin sensitivity by increasing adiponectin secretion. Further, Becn1 enhances adiponectin secretion by interacting with components of the exocyst complex via the coiled-coil domain. Together, our study demonstrates that Becn1 improves insulin sensitivity by facilitating adiponectin secretion through binding the exocyst in adipose tissue.
自噬失调与代谢疾病有关，包括 2 型糖尿病。然而，自噬机制如何调节代谢在很大程度上尚不清楚。自噬通常被认为是通过溶酶体进行的降解过程。在这里，我们揭示了一种在脂肪组织中由必需的自噬蛋白 Becn1 调控的代谢相关的非细胞自主的、非降解性的机制。在高脂肪饮食的挑战下，自噬过度活跃的 Becn1 小鼠通过脂联素介导的非细胞自主机制表现出全身胰岛素敏感性的系统改善，以及 AMP 激活的蛋白激酶（AMPK）的激活增强，而脂联素是一种脂肪组织来源的代谢激素。脂肪组织特异性 Becn1 的表达足以通过增加脂联素的分泌来激活非脂肪组织中的 AMPK，并改善全身胰岛素敏感性。此外，Becn1 通过卷曲螺旋结构域与外泌体复合物的成分相互作用来增强脂联素的分泌。总之，我们的研究表明，Becn1 通过在脂肪组织中结合外泌体促进脂联素的分泌来改善胰岛素敏感性。
