Rats Bred For High Aerobic Fitness Are Protected From Ovariectomy-induced Insulin Resistance During Euglycemic Clamp

Abstract

Ovariectomized (OVX) rodents model human menopause such that they develop metabolic dysfunction including reduced insulin sensitivity (i.e., insulin resistance (IR)) and increased adiposity. How aerobic fitness per se might protect against OVX-associated IR is not known. PURPOSE: To determine whether rats bred for high intrinsic aerobic fitness (HCR) are protected against OVX-induced IR using the gold standard euglycemic hyperinsulinemic clamp procedure, compared to rats bred for low intrinsic aerobic capacity (LCR). METHODS: Female HCR and LCR rats (n=40; age 22 wk) received OVX or sham-surgery (SHM) (groups: HCRSHM, HCROVX, LCRSHM, and LCROVX (n=10/group)). All rats underwent the clamp procedure 27 weeks following surgery. Following recovery from surgical catheterization of arterial and venous lines (3-5 days), rats were fasted for 5 hours and tested with the euglycemic hyperinsulinemic clamp to assess whole body insulin sensitivity. During the clamps, insulin was continuously infused at 4 mU/kg/min and blood samples were collected every 10min for an hour. Following the clamp procedure, a bolus of 14C-2-deoxyglucose (2DOG) was infused for the tissue-specific assessment of glucose uptake. Visceral (perigonadal, omental, and epididymal) and brown adipose tissue depots, and skeletal muscle samples were harvested 25 min following an infusion of 2DOG. RESULTS: While no differences in fasting glucose levels were found, glucose infusion rate (GIR) was lower in LCRSHM compared to HCRSHM (16.6±2.6 vs. 21.9±4.0 mg/kg/min, respectively; p<0.05) and LCR experienced a further reduction in GIR following OVX (-36%, p<0.05) compared to LCRSHM. In contrast, HCR did not exhibit a significant change in GIR following OVX. OVX increased body weight gain (HCR: +10%, LCR: +20%; p<0.05) and visceral adiposity (HCR: +30%, LCR: +62%; p<0.05) regardless of aerobic capacity. CONCLUSION: HCR rats were only slightly protected against OVX-associated gain in adiposity but were completely protected against OVX-associated insulin resistance. Analyses are underway to determine tissue-specific differences in glucose handling between groups in order to gain better mechanistic insight about the protection conferred by intrinsic fitness in this rodent model of menopause.