4.8 Article

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

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ADVANCED SCIENCE
卷 -, 期 -, 页码 -

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WILEY
DOI: 10.1002/advs.202305042

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bone metabolism; microgravity; neuropeptide Y (NPY); skeletal interoception; tyrosine hydroxylase (TH)

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Microgravity in spaceflight has a primary impact on human physiology, particularly bone loss and disturbances in the central nervous system. This research reveals that hindlimb unloading in mice stimulates the expression of neuropeptide Y (NPY) and tyrosine hydroxylase (TH) in the hypothalamus, leading to bone loss and altered fat metabolism. The reduced prostaglandin E2 (PGE2)-mediated interoceptive signaling of skeletal interoception is the underlying mechanism. Sympathetic antagonist propranolol or deletion of Adrb2 in osteocytes can rescue bone loss in this unloading model. Additionally, depletion of TH+ sympathetic nerves or inhibition of norepinephrine release can improve bone resorption. Inhibiting NPY expression in hypothalamic neurons reduces food intake and alters energy expenditure, while its effect on bone is limited. This indicates that the hypothalamic neuroendocrine factor NPY facilitates bone formation through the activity of sympathetic TH.
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.image

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