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Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons

Author

Listed:
  • Seul Ki Kim

    (Yonsei University College of Dentistry
    Yonsei University College of Dentistry)

  • Le Trung Tran

    (Yonsei University College of Dentistry
    Yonsei University College of Dentistry)

  • Cherl NamKoong

    (Seoul National University College of Medicine)

  • Hyung Jin Choi

    (Seoul National University College of Medicine
    Seoul National University College of Medicine)

  • Hye Jin Chun

    (Yonsei University College of Medicine)

  • Yong-ho Lee

    (Yonsei University College of Medicine)

  • MyungHyun Cheon

    (Konkuk University)

  • ChiHye Chung

    (Konkuk University)

  • Junmo Hwang

    (Korea Brain Research Institute (KBRI))

  • Hyun-Ho Lim

    (Korea Brain Research Institute (KBRI))

  • Dong Min Shin

    (Yonsei University College of Dentistry
    Yonsei University College of Dentistry)

  • Yun-Hee Choi

    (Yonsei University College of Dentistry)

  • Ki Woo Kim

    (Yonsei University College of Dentistry
    Yonsei University College of Dentistry)

Abstract

Small humanin-like peptide 2 (SHLP2) is a mitochondrial-derived peptide implicated in several biological processes such as aging and oxidative stress. However, its functional role in the regulation of energy homeostasis remains unclear, and its corresponding receptor is not identified. Hereby, we demonstrate that both systemic and intracerebroventricular (ICV) administrations of SHLP2 protected the male mice from high-fat diet (HFD)-induced obesity and improved insulin sensitivity. In addition, the activation of pro-opiomelanocortin (POMC) neurons by SHLP2 in the arcuate nucleus of the hypothalamus (ARC) is involved in the suppression of food intake and the promotion of thermogenesis. Through high-throughput structural complementation screening, we discovered that SHLP2 binds to and activates chemokine receptor 7 (CXCR7). Taken together, our study not only reveals the therapeutic potential of SHLP2 in metabolic disorders but also provides important mechanistic insights into how it exerts its effects on energy homeostasis.

Suggested Citation

  • Seul Ki Kim & Le Trung Tran & Cherl NamKoong & Hyung Jin Choi & Hye Jin Chun & Yong-ho Lee & MyungHyun Cheon & ChiHye Chung & Junmo Hwang & Hyun-Ho Lim & Dong Min Shin & Yun-Hee Choi & Ki Woo Kim, 2023. "Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40082-7
    DOI: 10.1038/s41467-023-40082-7
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    References listed on IDEAS

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    1. Joseph C. Reynolds & Rochelle W. Lai & Jonathan S. T. Woodhead & James H. Joly & Cameron J. Mitchell & David Cameron-Smith & Ryan Lu & Pinchas Cohen & Nicholas A. Graham & Bérénice A. Benayoun & Troy , 2021. "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
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    Cited by:

    1. Sheng Qiu & Qinan Wu & Hao Wang & Dongfang Liu & Chen Chen & Zhiming Zhu & Hongting Zheng & Gangyi Yang & Ling Li & Mengliu Yang, 2024. "AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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