2. Academic Validation
  3. Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons

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

  • Nat Commun. 2023 Jul 19;14(1):4321. doi: 10.1038/s41467-023-40082-7.
Seul Ki Kim 1 2,  Le Trung Tran 1 2,  Cherl NamKoong 3,  Hyung Jin Choi 3 4,  Hye Jin Chun 5,  Yong-Ho Lee 5,  MyungHyun Cheon 6,  ChiHye Chung 6,  Junmo Hwang 7,  Hyun-Ho Lim 7,  Dong Min Shin 1 2,  Yun-Hee Choi 1,  Ki Woo Kim 8 9
Affiliations

Affiliations

  • 1 Division of Physiology, Department of Oral Biology, Yonsei University College of Dentistry, Seoul, 03722, Korea.
  • 2 Department of Applied Life Science, BK21 FOUR, Yonsei University College of Dentistry, Seoul, 03722, Korea.
  • 3 Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea.
  • 4 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.
  • 5 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722, Korea.
  • 6 Department of Biological Sciences, Konkuk University, Seoul, 05029, Korea.
  • 7 Neurovascular Unit Research Group, Korea Brain Research Institute (KBRI), Daegu, 41068, Korea.
  • 8 Division of Physiology, Department of Oral Biology, Yonsei University College of Dentistry, Seoul, 03722, Korea. kiwoo-kim@yuhs.ac.
  • 9 Department of Applied Life Science, BK21 FOUR, Yonsei University College of Dentistry, Seoul, 03722, Korea. kiwoo-kim@yuhs.ac.
PMID: 37468558 DOI: 10.1038/s41467-023-40082-7
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.

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