PRMT4 Facilitates White Adipose Tissue Browning and Thermogenesis by Methylating PPARγ

  • Diabetes. 2023 Aug 1;72(8):1095-1111. doi: 10.2337/db22-1016.
Yi Zhong  1  2 ,  Yilong Wang  3 ,  Xiaoguang Li  1 ,  Haojie Qin  1  4 ,  Shu Yan  5 ,  Caijun Rao  6 ,  Di Fan  1  4 ,  Duqiu Liu  1  7 ,  Fei Deng  8 ,  Yanli Miao  9 ,  Ling Yang  1  2 ,  Kai Huang  1  4  10  11
Affiliations
  • 1. Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3. Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 4. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5. Heart Center and Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 6. Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 7. Liyuan Cardiovascular Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 8. Department of Urology, The Second Xiangya Hospital, Central South University, Hunan, China.
  • 9. Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 10. Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Huazhong University of Science and Technology, Wuhan, China.
  • 11. Hubei Clinical Research Center of Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology,Wuhan, China.
PMID: 37216643 DOI: 10.2337/db22-1016
Abstract

Obesity is a global health threat, and the induction of white adipose tissue (WAT) browning presents a promising therapeutic method for it. Recent publications revealed the essential role of protein arginine methyltransferase 4 (PRMT4) in lipid metabolism and adipogenesis, but its involvement in WAT browning has not been investigated. Our initial studies found that the expression of PRMT4 in adipocytes was upregulated in cold-induced WAT browning but downregulated in obesity. Besides, PRMT4 overexpression in inguinal adipose tissue accelerated WAT browning and thermogenesis to protect against high-fat diet-induced obesity and metabolic disruptions. Mechanistically, our work demonstrated that PRMT4 methylated peroxisome proliferator-activated receptor-γ (PPARγ) on Arg240 to enhance its interaction with the coactivator PR domain-containing protein 16 (PRDM16), leading to the increased expression of thermogenic genes. Taken together, our results uncover the essential role of the PRMT4/PPARγ/PRDM16 axis in the pathogenesis of WAT browning.

Article highlights: Protein arginine methyltransferase 4 (PRMT4) expression was upregulated during cold exposure and negatively correlated with body mass of mice and humans. PRMT4 overexpression in inguinal white adipose tissue of mice improved high-fat diet-induced obesity and associated metabolic impairment due to enhanced heat production. PRMT4 methylated peroxisome proliferator-activated receptor-γ on Arg240 and facilitated the binding of the coactivator PR domain-containing protein 16 to initiate adipose tissue browning and thermogenesis. PRMT4-dependent methylation of peroxisome proliferator-activated receptor-γ on Arg240 is important in the process of inguinal white adipose tissue browning.

Products