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

Research Paper

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

Pengbo Lou1#, Xueyun Bi1#, Yuhua Tian1#, 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 Zhang5✉, Huiyuan Guo2✉, Zhengquan Yu1✉

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.

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Citation:
Lou P, Bi X, Tian Y, Li G, Kang Q, Lv C, Song Y, Xu J, Sheng X, Yang X, Liu R, Meng Q, Ren F, Plikus MV, Liang B, Zhang B, Guo H, Yu Z. MiR-22 modulates brown adipocyte thermogenesis by synergistically activating the glycolytic and mTORC1 signaling pathways. Theranostics 2021; 11(8):3607-3623. doi:10.7150/thno.50900. Available from https://www.thno.org/v11p3607.htm

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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