Mice with targeted deletion of GH receptor (GHRKO mice) are GH resistant, small, hypoinsulinemic, very sensitive to insulin and remarkably long-lived. We have previously reported that these animals failed to respond to calorie restriction (CR) by additional increase in insulin sensitivity or extension of longevity. Because GHRKO mice are characterized by increased adiposity and adiposity is normally associated with insulin resistance rather than sensitivity, we hypothesized that the impact of adipose tissue on metabolism must be profoundly altered in these animals. To test this hypothesis, we compared the effects of surgical removal of visceral (epididymal and perinephric) fat in GHRKO and normal males.
Visceral fat removal (VFR) enhanced insulin sensitivity (assessed by insulin levels and insulin and glucose tolerance tests) and reduced intramuscular fat content, body temperature and respiratory quotient in normal animals but had disparate, generally opposite effects on the same parameters in GHRKO mice. Moreover, VFR in GHRKO but not normal mice reduced circulating levels of adiponectin, which is known to promote insulin sensitivity and exert anti-inflammatory effects. Functional differences between VF from normal and GHRKO mice implied by these findings were confirmed by measurements of lipolysis, adiponectin and iterleukin-6 levels and expression of genes related to fat metabolism.
We conclude that in the absence of GH signals, VF acts to promote insulin sensitivity rather than resistance. Lack of beneficial effects of VFR on insulin signaling and longevity-associated traits in GHRKO mice may explain why CR, which drastically reduces adiposity, failed to improve insulin sensitivity or extend longevity in these animals.
Supported by grants from the National Institute on Aging.