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

Abstract

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.

Brain regulates weight bearing bone through PGE2 skeletal interoception: implication of ankle osteoarthritis and pain

“…Bone mass and cortical bone of the talus decreased significantly in HU mice while body weight remained unchanged over time relative to their grounded littermate controls (Fig. 1e ) 41 . Again, the number of osteoblasts in the talus decreased significantly in the HU mice compared to the controls (Fig.…”

Mechanosensitive protein polycystin-1 promotes periosteal stem/progenitor cells osteochondral differentiation in fracture healing

“…HU Animal Model: For HU model after unilateral femoral fracture, suspending the hind limbs mimicked the microgravity or disuse conditions as previously reported 5 , 52 , 53 . One day after fracture modeling, 8 - to 10-week-old male (age-matched) genotype-matched mice were randomly separated into HU or ground controls.…”

“…Approximately 160-190 million new bone fractures occur each year, and despite advances in surgical treatments, 5-10% of patients suffer from impaired healing 1 , 2 . Decreased loading stimuli, e.g., lack of mechanical loading in the setting of prolonged bed rest and paralysis, result in reduced bone healing capacity, leading to delayed fusion or nonunion 3 - 5 . However, the underlying mechanism of mechanical stimuli regulating the fracture healing remains incompletely understood.…”

“…Advances in mechano-transduction have provided new insights into understanding how cells respond to the mechanical properties of the bone microenvironment 5 , 23 - 26 . Polycystin-1 (PC1), a large transmembrane protein encoded by the Pkd1 gene, exhibits unique functions due to its extracellular domain that acts as a sensor to mechanical stimuli and an intracellular domain that forms a complex with PC2 and TAZ to transmit signals to the cell 27 - 30 .…”

Cellular and Molecular Effects of Microgravity on the Immune System: A Focus on Bioactive Lipids

“…In particular, prostaglandin transporter gene SLCO2A1 was shown to undergo significant downregulation in HUVEC and EA.hy926 cells exposed to clinostat-simulated microgravity [57], while PGE 2 has been suggested as an important player in the molecular mechanisms behind microgravity-induced modifications. Indeed, Guo and colleagues have recently reported that PGE 2 is secreted by osteoblasts under mechanical loading, or in conditions of low bone density, and controls bone density and fat metabolism by triggering hypothalamic expression of tyrosine hydroxylase (TH) and of neuropeptide Y (NPY) through the EP4-expressing sensory nerves of ascending interoceptive pathways [58][59][60]. With regard to this, the authors have shown that hindlimb suspension leads to PGE2/EP4-mediated signaling in sensory interoceptive pathways, which leads to bone loss and adipose tissue lipolysis [60] Apparently, microgravity also acts by altering membrane balance and ion permeability through the function of Ca 2+ channels [61,62].…”