Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis

Zihan Yu; Xianju Li; Yanni Quan; Jiawen Chen; Jiarui Liu; Nairen Zheng; Shuwen Liu; Yini Wang; Wanlin Liu; Chen Qiu; Yi Wang; Ruimao Zheng; Jun Qin

doi:10.1016/j.celrep.2024.114142

Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis

Cell Rep. 2024 Apr 30;43(5):114142. doi: 10.1016/j.celrep.2024.114142. Online ahead of print.

Authors

Zihan Yu¹, Xianju Li², Yanni Quan², Jiawen Chen², Jiarui Liu³, Nairen Zheng², Shuwen Liu², Yini Wang², Wanlin Liu², Chen Qiu², Yi Wang², Ruimao Zheng³, Jun Qin⁴

Affiliations

¹ Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China.
² State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China.
³ Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China.
⁴ Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China. Electronic address: jqin1965@126.com.

PMID: 38691458
DOI: 10.1016/j.celrep.2024.114142

Abstract

Despite medical advances, there remains an unmet need for better treatment of obesity. Itaconate, a product of the decarboxylation of the tricarboxylic acid cycle intermediate cis-aconitate, plays a regulatory role in both metabolism and immunity. Here, we show that itaconate, as an endogenous compound, counteracts high-fat-diet (HFD)-induced obesity through leptin-independent mechanisms in three mouse models. Specifically, itaconate reduces weight gain, reverses hyperlipidemia, and improves glucose tolerance in HFD-fed mice. Additionally, itaconate enhances energy expenditure and the thermogenic capacity of brown adipose tissue (BAT). Unbiased proteomic analysis reveals that itaconate upregulates key proteins involved in fatty acid oxidation and represses the expression of lipogenic genes. Itaconate may provoke a major metabolic reprogramming by inducing fatty acid oxidation and suppression of fatty acid synthesis in BAT. These findings highlight itaconate as a potential activator of BAT-mediated thermogenesis and a promising candidate for anti-obesity therapy.

Keywords: CP: Metabolism; brown adipocyte; itaconate; obesity; proteomics; thermogenesis.