Energy homeostasis and adipose tissue metabolism are regulated in large part through peripheral sympathetic nerve innervation of metabolically important tissues and organs. This neural communication from the brain to adipose tissues results in release of the neurotransmitter norepinephrine that regulates energy expenditure through modulation of lipolysis, adipogenesis, ‘browning’ (development of brown adipocytes in white adipose depots), and non-shivering thermogenesis. Subcutaneous white adipose tissue (scWAT) is an energy storing tissue that is highly plastic, responding to metabolic need by changing mass and cellularity, as well as responding to challenges (including cold temperature, exercise, fasting) by modifying neural activity and metabolism. Within scWAT lies a dense bed of nerves and blood vessels that are integrated closely, and in large part, rely on one another to function properly. Even if not directly innervating the blood vessels themselves (as is the case with capillaries), neurites that appear to innervate single adipocytes use these blood vessels as scaffolding to traverse the tissue. We have recently demonstrated that under pathological conditions (obesity and aging), scWAT innervation decreases through a process termed ‘adipose neuropathy’. With advanced age the small fiber peripheral nerve endings in adipose die back, including reducing contact with adipose-resident blood vessels (as observed previously in the C57BL6/J mouse). This likely poses a physiological challenge for metabolism and for vascular or adipose tissue health and function. For this work, we compared C57BL6/J mice with the more genetically diverse HET3 mouse model, established for the NIA’s Intervention Testing Program to more accurately represent the variability of age-related mortality/morbidity. We investigated incidence of peripheral neuropathy with aging (skin, scWAT muscle) as well as changes to the neurovascular supply of scWAT across several ages in both males and females. We also investigated the anti-aging drug Rapamycin as a potential means to prevent or reduce adipose neuropathy. We found that HET3 mice display a reduced neuropathy phenotype compared to inbred C56BL6/J mice. Importantly, the nerve die-back around blood vessels was not observed in the HET3 model. However, male HET3 mice did reveal neuropathic phenotypes by 62wks of age, characterized by decreased mechanoreception in hind paw skin, reduced NMJ occupation, and decreased expression of the Schwann cell marker
Sox10
in scWAT. Female HET3 mice appeared to have increased protection from neuropathy until advanced age (126wks) when they began to show stronger phenotypes than males (excluding
Sox10
analysis.) Despite its success as a longevity treatment in mice, rapamycin had little to no effect on reducing or preventing the onset of adipose neuropathy.
The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis
