SIRT3 Acts as a Positive Autophagy Regulator to Promote Lipid Mobilization in Adipocytes via Activating AMPK.

Tian Zhang,Qiang Tong,Ligen Lin,Jingxin Liu

doi:10.3390/ijms21020372

Abstract

Obesity is increasing at an alarming rate worldwide, which is characterized by the excessive accumulation of triglycerides in adipocytes. Emerging evidence has demonstrated that macroautophagy and chaperone-mediated autophagy (CMA) regulate lipid mobilization and play a key role in energy balance. Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase, which is important in regulating macroautophagy and lipid metabolism. It is still unknown whether SIRT3 modulates macroautophagy and CMA in adipocytes. The current study found that macroautophagy was dynamically regulated during 3T3-L1 adipocyte differentiation, which coincided with SIRT3 expression. In mature adipocytes, overexpression of SIRT3 activated macroautophagy, mainly on lipid droplets (LDs), through activating the AMP-activated protein kinase (AMPK)-unc-51-like kinase 1 (ULK1) pathway, which in turn resulting in smaller LD size and reduced lipid accumulation. Moreover, SIRT3 overexpression induced the formation of perilipin-1 (PLN1)-heat shock cognate 71 kDa protein (HSC70)-lysosome-associated membrane protein 2 (LAMP2) complex, to activate CMA and cause the instability of LDs in adipocytes. In summary, we found SIRT3 is a positive regulator of macroautophagy and CMA in adipocytes, which might be a promising therapeutic target for treatment of obesity and its related metabolic dysfunction.

Highlights

The global prevalence of obesity has increased substantially over the past decades [1], which is positively relevant to cardiovascular diseases [2], type 2 diabetes [3], and certain types of cancer [4]
The Sirtuin 3 (SIRT3) expression was relatively high at the initial stage of adipocyte differentiation and declined from four days post hormonal stimulation, which coincided with the change pattern of macroautophagy (Figure 1b)
Impaired macroautophagy leads to excessive lipid accumulation in the liver to cause hepatic steatosis [33], and alters fatty acid metabolism to reduce cause hepatic steatosis [33], and alters fatty acid metabolism to reduce mass of white adipose tissue (WAT) [14]

Summary

Introduction

The global prevalence of obesity has increased substantially over the past decades [1], which is positively relevant to cardiovascular diseases [2], type 2 diabetes [3], and certain types of cancer [4]. The storage and mobilization of lipids in adipocytes are essential to maintain energy balance. The excessive energy is converted into triglycerides (TGs) and deposited in lipid droplets (LDs) in adipocytes, resulting in the expansion of white adipose tissue (WAT) [5,6]. A moderate activation of macroautophagy leads to decrease the body weight of mice [11]. These studies demonstrate the complicated roles of macroautophagy in regulating lipid storage and mobilization. Macroautophagy regulates cytoplasmic remodeling and mitochondrial turnover in the process of adipogenesis. Suppression of macroautophagy blocks adipogenesis, and reduces the formation of large LDs in adipocytes [12,13]. The involvement of macroautophagy in adipogenesis and lipid turnover is still controversial

Methods

Results

Conclusion