Survivin is essential for thermogenic program and metabolic homeostasis in mice

Miriayi Alimujiang; Jingjing Sun; Shuqing Chen; Ningning Bai; Shuqin Chen; Fan Hu; Jingyuan Ma; Yuejie Xu; Jun Xu; Xiaojing Ma; Ying Yang

doi:10.1016/j.molmet.2022.101446

Survivin is essential for thermogenic program and metabolic homeostasis in mice

Mol Metab. 2022 Apr:58:101446. doi: 10.1016/j.molmet.2022.101446. Epub 2022 Jan 31.

Authors

Miriayi Alimujiang¹, Jingjing Sun¹, Shuqing Chen¹, Ningning Bai¹, Shuqin Chen¹, Fan Hu¹, Jingyuan Ma², Yuejie Xu², Jun Xu³, Xiaojing Ma⁴, Ying Yang⁵

Affiliations

¹ Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China; Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai, China.
² Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai, China.
³ Department of Geriatrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
⁴ Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China; Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai, China. Electronic address: maxiaojing@sjtu.edu.cn.
⁵ Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China; Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai, China. Electronic address: yangyingsh@sjtu.edu.cn.

Abstract

Objective: Survivin is a member of the inhibitor of apoptosis family. Our previous study showed that survivin expression could be strongly induced by long-term, high-fat diet (HFD) exposure in vivo. It could also be induced by insulin through the PI3K/mTOR signaling pathway in vitro. Therefore, we hypothesized that under certain conditions, survivin expression might be required for adipocyte function. In the current study, we aim to further investigate the regulation of survivin expression in mature adipocytes upon various nutritional stimuli and the role of survivin using adipocyte-specific survivin knockout (SKO) mice.

Methods: SKO mice were obtained by crossing survivin^flox/flox mice with Adiponectin-Cre^+/- mice. The overall metabolic phenotype was observed under chow diet (CD) and HFD feeding conditions. The thermogenic program of mice was detected upon cold exposure. The inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT) stromal vascular fraction cells were isolated and differentiated into mature adipocytes, and the effects of survivin deletion on mature adipocyte function were detected in vitro.

Results: Survivin expression in adipose tissue and adipocytes was regulated by short-term nutritional stress both in vivo and in vitro. The postnatal development of BAT was impaired in SKO mice, which resulted in drastically reduced BAT mass and decreased expression of the thermogenic protein Ucp1 in 24-week-old mice fed with CD. After HFD feeding, the iWAT and BAT mass of SKO mice were significantly decreased, causing ectopic lipid accumulation in the liver, which was associated with insulin resistance and glucose intolerance. Upon cold exposure, the expression of thermogenic genes and proteins was markedly reduced in BAT and iWAT of SKO mice, accompanied by abnormal mitochondrial structure and induced autophagy. Consistently, thermogenic program and mitochondrial oxidative phosphorylation were reduced in survivin-depleted brown and beige adipocytes in vitro.

Conclusions: Our findings showed that survivin could be regulated by nutritional stress in adipocytes and revealed a new role of survivin in maintaining normal BAT mass and positively regulating the thermogenic program and mitochondrial oxidative phosphorylation.

Keywords: Autophagy; Brown adipose tissue development; Obesity; Survivin; Thermogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes, Brown* / metabolism
Adipose Tissue, Brown* / metabolism
Animals
Homeostasis
Mice
Mice, Knockout
Survivin / metabolism

Substances

Birc5 protein, mouse
Survivin