Amongst the better known genetic longevity enhancements in mice is GHRKO, or growth hormone receptor knockout. The gene that encodes the growth hormone receptor protein is deleted, and as a consequence these mice live a lot longer than their peers - but only if well cared for, as they have trouble maintaining their body temperature. Unexpectedly, they are also obese, while at the same time exhibiting a biochemistry that is very uncharacteristic for obese mice. GHRKO mice are not in the slightest bit insulin resistant, for example, which is the otherwise normal end result of obesity in mammals, leading to metabolic syndrome and type 2 diabetes.
If you're a regular reader, you'll know that excess visceral fat is bad for you, and the more of it you have and the longer you keep it, the worse the end result. It significantly raises your risk of suffering all of the common age-related conditions, and shortens your life expectancy to boot. So don't get fat and don't stay fat is good advice for nearly everyone.
research showed that for those who had a medium number of years lived with obesity (between five years and 14.9 years), the risk of mortality more than doubled than for those who had never been obese. The risk of mortality almost tripled for those with the longest duration of obesity (more than 15 years). Furthermore, the research showed for every additional two years lived with obesity, the risk of mortality increased by between six and seven per cent.
Interestingly enough, surgical removal of visceral fat extends life in ordinary mice. But if you do the same to GHRKO mice, it actually harms their health. As a recent paper shows, the removal of that growth hormone receptor dramatically changes the biochemistry of visceral fat, switching it from being a net harm to a net benefit.
Mice with targeted deletion of the growth hormone receptor (GHRKO mice) are GH resistant, small, obese, hypoinsulinemic, highly insulin sensitive and remarkably long-lived. To elucidate the unexpected coexistence of adiposity with improved insulin sensitivity and extended longevity, we examined effects of surgical removal of visceral (epididymal and perinephric) fat on metabolic traits related to insulin signaling and longevity.
Comparison of results obtained in GHRKO mice and in normal animals from the same strain revealed disparate effects of visceral fat removal (VFR) on insulin and glucose tolerance, adiponectin levels, accumulation of ectopic fat, phosphorylation of insulin signaling intermediates, body temperature and respiratory quotient (RQ). Overall, VFR produced the expected improvements in insulin sensitivity and reduced body temperature and RQ in normal mice and had opposite effects in GHRKO mice.
We conclude that in the absence of GH signaling the secretory activity of visceral fat is profoundly altered and unexpectedly promotes enhanced insulin sensitivity. The apparent beneficial effects of visceral fat in GHRKO mice may also explain why reducing adiposity by calorie restriction fails to improve insulin signaling or further extend longevity in these animals.
As the researchers note, this sheds light on a few previously puzzling observations.