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Theranostics 2021; 11(8):3607-3623. doi:10.7150/thno.50900 This issue Cite

Research Paper

MiR-22 modulates brown adipocyte thermogenesis by synergistically activating the glycolytic and mTORC1 signaling pathways

Pengbo Lou^1#, Xueyun Bi^1#, Yuhua Tian^1#, Guilin Li¹, Qianqian Kang¹, Cong Lv¹, Yongli Song¹, Jiuzhi Xu¹, Xiaole Sheng¹, Xu Yang¹, Ruiqi Liu¹, Qingyong Meng¹, Fazheng Ren², Maksim V. Plikus³, Bin Liang⁴, Bing Zhang^5✉, Huiyuan Guo^2✉, Zhengquan Yu^1✉

1. State Key Laboratories for Agrobiotechnology and Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, College of Biological Sciences, China Agricultural University, Beijing, China, 100193.
2. Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, College of Food Sciences and nutritional engineering, China Agricultural University, Beijing, China, 100083.
3. Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research, Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA.
4. Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan, China, 650091.
5. College of Veterinary Medicine, China Agricultural University, Beijing, China.
#Shared co-first authorship.

✉ Corresponding authors: E-mail: zyuedu.cn (Zhengquan Yu, lead contact); guohuiyuanedu.cn (Huiyuan Guo); zhangdbedu.cn (Bing Zhang).

Abstract

Background: Brown adipose tissue (BAT) dissipates chemical energy as heat and has the potential to be a protective strategy to prevent obesity. microRNAs (miRNAs) are emerging as important posttranscriptional factors affecting the thermogenic function of BAT. However, the regulatory mechanism underlying miRNA-mediated energy metabolism in BAT is not fully understood. Here, we explored the roles of miR-22 in BAT thermogenesis and energy metabolism.

Methods: Using global and conditional knockout mice as in vivo models and primary brown adipocytes as an in vitro system, we investigated the function of miR-22 in BAT thermogenesis in vivo and in vitro.

Results: miR-22 expression was upregulated in BAT in response to cold exposure and during brown preadipocyte differentiation. Both global and conditional knockout mice displayed BAT whitening, impaired cold tolerance, and decreased BAT thermogenesis. Moreover, we found that miR-22 deficiency impaired BAT glycolytic capacity, which is critical for thermogenesis. The mechanistic results revealed that miR-22 activated the mTORC1 signaling pathway by directly suppressing Tsc1 and concomitantly directly suppressing Hif1an, an inhibitor of Hif1α, which promotes glycolysis and maintains thermogenesis.

Conclusions: Our findings identify miR-22 as a critical regulator in the control of thermogenesis in BAT and as a potential therapeutic target for human metabolic disorders.

Keywords: miR-22, BAT, thermogenesis, glycolysis, mTORC1

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