Open AccessACSS3 in brown fat drives propionate catabolism and its deficiency leads to autophagy and systemic metabolic dysfunction
Author(s) -
Jia Zhihao,
Chen Xiyue,
Chen Jingjuan,
Zhang Lijia,
Oprescu Stephanie N.,
Luo Nanjian,
Xiong Yan,
Yue Feng,
Kuang Shihuan
Publication year - 2022
Publication title -
clinical and translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
H-Index - 1
ISSN - 2001-1326
DOI - 10.1002/ctm2.665
Subject(s) - endocrinology , medicine , insulin resistance , white adipose tissue , autophagy , propionate , adipocyte , brown adipose tissue , adipose tissue , biology , chemistry , insulin , biochemistry , apoptosis
Propionate is a gut microbial metabolite that has been reported to have controversial effects on metabolic health. Here we show that propionate is activated by acyl‐CoA synthetase short‐chain family member 3 (ACSS3), located on the mitochondrial inner membrane in brown adipocytes. Knockout of Acss3 gene (Acss3 –/– ) in mice reduces brown adipose tissue (BAT) mass but increases white adipose tissue (WAT) mass, leading to glucose intolerance and insulin resistance that are exacerbated by high‐fat diet (HFD). Intriguingly, Acss3 –/– or HFD feeding significantly elevates propionate levels in BAT and serum, and propionate supplementation induces autophagy in cultured brown and white adipocytes. The elevated levels of propionate in Acss3 –/– mice similarly drive adipocyte autophagy, and pharmacological inhibition of autophagy using hydroxychloroquine ameliorates obesity, hepatic steatosis and insulin resistance of the Acss3 –/– mice. These results establish ACSS3 as the key enzyme for propionate metabolism and demonstrate that accumulation of propionate promotes obesity and Type 2 diabetes through triggering adipocyte autophagy.