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Cell Rep. 2018 Jun 19;23(12):3607-3620. doi: 10.1016/j.celrep.2018.05.065.

An Hsp20-FBXO4 Axis Regulates Adipocyte Function through Modulating PPARγ Ubiquitination.

Author information

1
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
2
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
3
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
4
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
5
Samaritan Medical Center, Watertown, NY 13601, USA.
6
Lipidomics Research Program, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45219-0516, USA.
7
Critical Illness Research, Lawson Health Research Institute, London, ON N6A 4G5, Canada.
8
Sate Key Laboratory of Genetic Engineering, School of Life Sciences, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200438, China.
9
Divisions of Endocrinology and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: takahisa.nakamura@cchmc.org.
10
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China. Electronic address: huangkai1@hust.edu.cn.
11
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA. Electronic address: pereztdo@ucmail.uc.edu.
12
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Electronic address: fangg@ucmail.uc.edu.

Abstract

Exposure to cold temperature is well known to upregulate heat shock protein (Hsp) expression and recruit and/or activate brown adipose tissue and beige adipocytes in humans and animals. However, whether and how Hsps regulate adipocyte function for energy homeostatic responses is poorly understood. Here, we demonstrate a critical role of Hsp20 as a negative regulator of adipocyte function. Deletion of Hsp20 enhances non-shivering thermogenesis and suppresses inflammatory responses, leading to improvement of glucose and lipid metabolism under both chow diet and high-fat diet conditions. Mechanistically, Hsp20 controls adipocyte function by interacting with the subunit of the ubiquitin ligase complex, F-box only protein 4 (FBXO4), and regulating the ubiquitin-dependent degradation of peroxisome proliferation activated receptor gamma (PPARγ). Indeed, Hsp20 deficiency mimics and enhances the pharmacological effects of the PPARγ agonist rosiglitazone. Together, our findings suggest a role of Hsp20 in mediating adipocyte function by linking β-adrenergic signaling to PPARγ activity.

KEYWORDS:

FBXO4; Hsp20; PPARγ; lipogenesis; thermogenesis; ubiquitination

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