As people age, "middle-age weight gain" has become a widespread health problem and a major risk factor for metabolic diseases such as type 2 diabetes and cardiovascular disorders. However, the molecular mechanisms underlying this phenomenon remain incompletely understood.

In a study published in Nature Communications on February 23, researchers from the Institute of Biophysics of the Chinese Academy of Sciences, in collaboration with Zhengzhou Central Hospital Affiliated to Zhengzhou University, identified S-nitrosoglutathione reductase (GSNOR) as a novel gene linked to age-related obesity for the first time.

They revealed a previously unknown mechanism by which GSNOR drives adipose tissue "whitening" through the regulation of protein S-nitrosation, thereby promoting age-related obesity, and highlights GSNOR as a potential therapeutic target.

The researchers first discovered that GSNOR expression is significantly higher in the subcutaneous adipose tissue of middle-aged humans and mice than in younger individuals.

Further investigations showed that deleting GSNOR completely protects mice from age-related weight gain, whereas overexpressing GSNOR specifically in adipose tissue leads to an early-onset obesity phenotype. These findings establish GSNOR as a new gene associated with age-related obesity.

Overexpression of GSNOR in adipose tissue resulted in increased accumulation of white fat, accompanied by a marked reduction in thermogenic beige adipocytes, which are responsible for energy expenditure. This shift toward "whitening" of subcutaneous adipose tissue is a key driver of weight gain in middle age.

Using quantitative proteomic analysis of protein S-nitrosation, the researchers identified a critical GSNOR target: Beclin-1, a protein that regulates autophagy.

GSNOR mediates the denitrosation of Beclin-1 at cysteine 351. This modification enhances the interaction between Beclin-1 and ATG14, thereby activating autophagy. However, excessive autophagy accelerates mitochondrial clearance within cells, leading to the loss of beige adipocyte characteristics, promoting adipose tissue whitening, and ultimately resulting in obesity.

Notably, knocking down GSNOR in the adipose tissue of 14-month-old middle-aged mice significantly increased adipose tissue beiging and decreased fat mass. These results demonstrate that targeting GSNOR offers a promising therapeutic approach with significant translational potential.

This study is the first to identify GSNOR as a gene associated with age-related obesity, revealing a new mechanism by which redox-dependent protein S-nitrosation regulates weight gain in middle age. Furthermore, it establishes GSNOR as a highly promising target for preventing and treating age-related obesity.

Schematic illustration of the molecular mechanism by which GSNOR promotes autophagy and induces adipose tissue whitening in age-related obesity. (Image by CHEN Chang's group)