Unloading‐Induced Skeletal Interoception Alters Hypothalamic Signaling to Promote Bone Loss and Fat Metabolism

• Published in: Advanced science Vol. 10; no. 35; pp. e2305042 - n/a
• Main Authors: Guo, Qiaoyue, Chen, Ningrong, Patel, Kalp, Wan, Mei, Zheng, Junying, Cao, Xu
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.12.2023; John Wiley and Sons Inc; Wiley
• Subjects: Bone density; Bone marrow; bone metabolism; Enzymes; Homeostasis; Hydrogels; Hypothalamus; Metabolism; microgravity; Musculoskeletal system; neuropeptide Y (NPY); Physiology; Quantitative analysis; skeletal interoception; tyrosine hydroxylase (TH); Weightlessness; microgravity; bone metabolism; tyrosine hydroxylase (TH); neuropeptide Y (NPY); skeletal interoception
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202305042

Microgravity is the primary factor that affects human physiology in spaceflight, particularly bone loss and disturbances of the central nervous system. However, little is known about the cellular and molecular mechanisms of these effects. Here, it is reported that in mice hindlimb unloading stimulates expression of neuropeptide Y (NPY) and tyrosine hydroxylase (TH) in the hypothalamus, resulting in bone loss and altered fat metabolism. Enhanced expression of TH and NPY in the hypothalamus occurs downstream of a reduced prostaglandin E2 (PGE2)‐mediated ascending interoceptive signaling of the skeletal interoception. Sympathetic antagonist propranolol or deletion of Adrb2 in osteocytes rescue bone loss in the unloading model. Moreover, depletion of TH+ sympathetic nerves or inhibition of norepinephrine release ameliorated bone resorption. Stereotactic inhibition of NPY expression in the hypothalamic neurons reduces the food intake with altered energy expenditure with a limited effect on bone, indicating hypothalamic neuroendocrine factor NPY in the facilitation of bone formation by sympathetic TH activity. These findings suggest that reduced PGE2‐mediated interoceptive signaling in response to microgravity or unloading has impacts on the skeletal and central nervous systems that are reciprocally regulated. During unloading, PGE2/EP4 ascending signal increases the expression of both sympathetic tone and NPY level in the hypothalamus. The elevated NE leads to bone loss while increased hypothalamic NPY acts as neuronal endocrine factor for the impaired metabolism.  The primary function of NPY is to regulate energy metabolism to facilitate bone formation.