Adipose-specific knockdown of <i>Sirt1</i> results in obesity and insulin resistance by promoting exosomes release

Abstract

Sirtuin1 (SIRT1) has recently emerged as a pivotal regulator of glucose metabolism and insulin sensitivity. However, the underlying mechanism has not been fully elucidated. In this study, we investigated the role of SIRT1 in the development of obesity and insulin resistance by generating mice with adipose-specific ablation of <i>Sirt1</i> (Ad-<i>Sirt1</i>^-/- mice). Ad-<i>Sirt1</i>^-/- mice exhibited increased fat mass, impaired glucose tolerance, attenuated insulin sensitivity, and increased exosomes, whereas the administration of exosomes inhibitor effectively ameliorated the impaired metabolic profile in Ad-<i>Sirt1</i>^-/- mice. Moreover, the increased exosomes were proved to be a result of defective autophagy activity in Ad-<i>Sirt1</i>^-/- mice and restoration of SIRT1 activity efficiently improved metabolic profiles <i>in vitro</i>. Further study demonstrated that <i>Sirt1</i> deficiency-induced exosomes modulated insulin sensitivity at least partially via the TLR4/NF-κB signaling pathway. Therefore, our findings implicated SIRT1 as a key factor in metabolic regulation, and adipose <i>Sirt1</i> deficiency could exert an effect on the development of obesity and insulin resistance by promoting exosome release.