Mevalonate biosynthesis pathway regulates the development and survival of brown adipocytes

Jungin Kwon; Yu-Sheng Yeh; Satoko Kawarasaki; Hiroto Minamino; Yoshihito Fujita; Yuko Okamatsu-Ogura; Haruya Takahashi; Wataru Nomura; Shigenobu Matsumura; Rina Yu; Kazuhiro Kimura; Masayuki Saito; Nobuya Inagaki; Kazuo Inoue; Teruo Kawada; Tsuyoshi Goto

doi:10.1016/j.isci.2023.106161

Mevalonate biosynthesis pathway regulates the development and survival of brown adipocytes

iScience. 2023 Feb 8;26(3):106161. doi: 10.1016/j.isci.2023.106161. eCollection 2023 Mar 17.

Authors

Jungin Kwon¹, Yu-Sheng Yeh¹, Satoko Kawarasaki¹, Hiroto Minamino², Yoshihito Fujita², Yuko Okamatsu-Ogura³, Haruya Takahashi¹, Wataru Nomura^{1

4}, Shigenobu Matsumura⁵, Rina Yu⁶, Kazuhiro Kimura³, Masayuki Saito³, Nobuya Inagaki², Kazuo Inoue^{1

4}, Teruo Kawada^{1

4}, Tsuyoshi Goto^{1

4}

Affiliations

¹ Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 611-0011, Japan.
² Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
³ Departments of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
⁴ Research Unit for Physiological Chemistry, the Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan.
⁵ Division of Clinical Nutrition, Graduate School of Comprehensive Rehabilitation, Osaka Prefecture University, Osaka 583-0872, Japan.
⁶ Department of Food Science and Nutrition, University of Ulsan, Ulsan 44610, Republic of Korea.

Abstract

The high thermogenic activity of brown adipose tissue (BAT) has received considerable attention. Here, we demonstrated the role of the mevalonate (MVA) biosynthesis pathway in the regulation of brown adipocyte development and survival. The inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme in the MVA pathway and the molecular target of statins, suppressed brown adipocyte differentiation by suppressing protein geranylgeranylation-mediated mitotic clonal expansion. The development of BAT in neonatal mice exposed to statins during the fetal period was severely impaired. Moreover, statin-induced geranylgeranyl pyrophosphate (GGPP) deficiency led to the apoptosis of mature brown adipocytes. Brown adipocyte-specific Hmgcr knockout induced BAT atrophy and disrupted thermogenesis. Importantly, both genetic and pharmacological inhibition of HMGCR in adult mice induced morphological changes in BAT accompanied by an increase in apoptosis, and statin-treated diabetic mice showed worsened hyperglycemia. These findings revealed that MVA pathway-generated GGPP is indispensable for BAT development and survival.

Keywords: Biochemistry; Biological sciences; Molecular Genetics.