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MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction

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Abstract

The postmenopausal state is associated with an increased risk of metabolic disorder including reduced energy expenditure and weight gain, leading to higher cardiovascular and cancer risks among other diseases. Mitochondrial-derived peptide (MOTS-c) is a 16–amino acid peptide encoded by mitochondrial DNA. Here, we showed that MOTS-c treatment in mice prevented ovariectomy-induced obesity and insulin resistance. After ovariectomy, low levels of estrogens increased fat mass overload and disturbed normal adipose function, forcing the development of insulin resistance. MOTS-c treatment increased brown fat activation and reduced OVX-induced fat accumulation and inflammatory invasion in white adipose tissue, which contributes to the lower level of fatty acid in serum and liver. Moreover, MOTS-c activated AMPK pathway to improve energy dissipation and insulin sensitivity. And a blocker of AMPK pathway was found to attenuate the role of MOTS-c in the regulation of adipocyte lipid metabolism. In conclusion, MOTS-c is a high potential candidate for chronic treatment of menopausal induced metabolic dysfunction.

Key messages

• MOTS-c prevents ovariectomy (OVX)-induced body weight gain and insulin resistance.

• MOTS-c reduces fat mass and suppresses inflammatory response under OVX condition.

• MOTS-c sustains the activity of the brown adipose under OVX condition.

• MOTS-c mediates AMPK pathway activation to control adipose metabolic homeostasis.

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Funding

This research was supported by the National Natural Science Foundation of China (NSF: 31571215; NSF: 31270843, NSF: 81330045; NSF: 81730053) and the Military Logistics Research Project (AWS14L008; AWS16J022).

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Author notes

  1. Huanyu Lu, Ming Wei and Yue Zhai contributed equally to this work.

Authors and Affiliations

  1. Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, No. 169 West Chang-le Road, Xi’an, 710032, Shaanxi, People’s Republic of China

    Huanyu Lu, Wenjing Luo & Jingyuan Chen

  2. Department of Pharmacology, Xi’an Medical University, Xi’an, Shaanxi, People’s Republic of China

    Ming Wei

  3. Department of Cell Biology, Air Force Medical University, No. 169 West Chang-le Road, Xi’an, 710032, Shaanxi, People’s Republic of China

    Yue Zhai

  4. Company 22, Brigade 6, School of Basic Medicine, Air Force Medical University, No. 169 West Chang-le Road, Xi’an, 710032, Shaanxi, People’s Republic of China

    Qingyang Li

  5. State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, Air Force Medical University, No. 169 West Chang-le Road, Xi’an, 710032, People’s Republic of China

    Zichen Ye, Li Wang & Zifan Lu

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  1. Huanyu Lu
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  2. Ming Wei
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  3. Yue Zhai
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  4. Qingyang Li
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Correspondence to Jingyuan Chen or Zifan Lu.

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Lu, H., Wei, M., Zhai, Y. et al. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. J Mol Med 97, 473–485 (2019). https://doi.org/10.1007/s00109-018-01738-w

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  • DOI: https://doi.org/10.1007/s00109-018-01738-w

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