Changes in adipose tissue's extracellular matrix, as with fibrosis, inhibits the tissue's ability to shrink and expand as needed, resulting in sheer stress on adipocytes and chronic inflammation, as well as decreased insulin sensitivity. With aging, a state of metabolic dysregulation and increased incidence of insulin resistance, we have observed a reduction in adipose innervation. This ‘adipose neuropathy' likely poses a physiological challenge for tissue metabolic function and glucose homeostasis, as has been observed in adipose denervation studies. Using second-harmonic generation label-free imaging of adipose collagen and advanced image co-localization techniques, we found that obese adipose tissue exhibits higher co-localization of nerves with collagen fibers, indicating that changes in tissue fibrosis may tie mechanistically with tissue neuropathy. We compared C57BL/6J mice with the more genetically diverse HET3 mouse model that is used by the NIA's intervention testing program, to investigate age-related neuropathy and adipose fibrosis. We found that HET3 mice displayed mitigated neuropathy phenotypes in skin, muscle and adipose, compared to inbred C56BL/6J mice. Tissue fibrosis was significantly increased with age in subcutaneous and visceral white adipose depots of both strains of mice. Using birefringence imaging, we found that the relative distribution of type I / thick filament collagen increased with age while type III / thin filament collagen decreased. Gene expression by qPCR revealed significant increases in collagen genes Col1a1, Col3a1, and Col5a1 in adipose with age. Despite its success as a longevity treatment, the mTOR inhibitor rapamycin had little to no effect on reducing or preventing the onset of neuropathy in HET3 aged mice, and importantly it worsened the fibrotic phenotype with increased type 1 collagen in adipose. Together, we found that rapamycin's longevity effects are uncoupled from healthspan producing effects, with detrimental impacts on adipose fibrosis that may impact age-related insulin resistance.
J. Willows: None. G. Mishra: None. M. Blaszkiewicz: None. K. L. Townsend: Other Relationship; Neuright, Inc.
American Heart Association (AHA) Collaborative Sciences Award (18CSA34090028)