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  3. Targeting MCH Neuroendocrine Circuit in Lateral Hypothalamus to Protect Against Skeletal Senescence

Targeting MCH Neuroendocrine Circuit in Lateral Hypothalamus to Protect Against Skeletal Senescence

  • Adv Sci (Weinh). 2024 Nov;11(43):e2309951. doi: 10.1002/advs.202309951.
Bin Guo 1,  Yong Zhu 1,  Shuai Lu 2 3,  Xiangming Chen 1,  Zhuoqun Ren 4,  Yuqi Liu 1,  Hao Luo 1,  Chao Wang 1,  Xucheng Yang 1,  Jianxi Zhu 1 5 6
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China.
  • 2 Department of Orthopedic Trauma, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China.
  • 3 Beijing Research Institute of Traumatology and Orthopaedics, Beijing, 100035, China.
  • 4 Xiangya School of Medicine, Central South University, Changsha, 410008, China.
  • 5 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, 410008, China.
  • 6 Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Hunan, 410008, China.
PMID: 39320347 DOI: 10.1002/advs.202309951
Abstract

Neuroendocrine regulation is essential for maintaining metabolic homeostasis. However, whether neuroendocrine pathway influence bone metabolism and skeletal senescence is unelucidated. Here, a central neuroendocrine circuit is identified that directly controls osteogenesis. Using virus based tracing, this study is identified that melanin concentrating hormone (MCH) expressing neurons in the lateral hypothalamus (LH) are connected to the bone. Chemogenetic activation of MCH neurons in the LH induces osteogenesis, whereas inhibiting these neurons reduces osteogenesis. Meanwhile, MCH is released into the circulation upon chemogenetic activation of these neurons. Single cell Sequencing reveals that blocking MCH neurons in the LH diminishes osteogenic differentiation of bone marrow stromal cells (BMSCs) and induces senescence. Mechanistically, MCH promotes BMSC differentiation by activating MCHR1 via PKA signaling, and activating MCHR1 by MCH agonists attenuate skeletal senescence in mice. By elucidating a brain-bone connection that autonomously enhances osteogenesis, these findings uncover the neuroendocrinological mechanisms governing bone mass regulation and protect against skeletal senescence.

Keywords

BMSC; lateral hypothalamus; melanin concentrating hormone; neuroendocrinology; osteogenesis; skeletal senescence.

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