Metabolic effects of intra‐abdominal fat in GHRKO mice

Abstract

SUMMARY 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. Some of the examined parameters were altered by VFR in opposite directions in GHRKO and normal mice, others were affected in only one genotype or exhibited significant genotype × treatment interactions. Functional differences between visceral fat of GHRKO and normal mice were confirmed by measurements of adipokine secretion, lipolysis and expression of genes related to fat metabolism. 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.

Long‐lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high‐fat diet on metabolic function and energy expenditure

“…Previous studies have indicated that long‐lived mice that either are GH‐deficient or exhibit disrupted GH signaling have increased adiposity and systemic high levels of adiponectin (Berryman et al ., 2004; Wang et al ., 2006). The removal of epididymal visceral fat decreased levels of adiponectin and reduced insulin sensitivity in GHR‐KO and Ames dwarf mice (Masternak et al ., 2012; Menon et al ., 2014). In the context that in the absence of GH signaling, visceral fat exerts unexpected beneficial influence on insulin sensitivity (Bartke, 2008), and in this study Ames dwarf mice are resistant to the detrimental effects of HFD, we were interested in determining whether transplantation of visceral fat from Ames dwarf mice fed HFD into control littermates fed the same diet could improve their insulin sensitivity.…”

“…These data complement the reports that the removal of both epididymal and perinephric WAT reduces insulin sensitivity in Ames dwarf (Menon et al ., 2014) and GHR‐KO mice (Masternak et al ., 2012) and suggest that the eWAT transplant from long‐lived mice improves metabolic function in control mice fed HFD hence aids in the protection against the effects of HFD‐induced metabolic dysfunction.…”

“…Ames dwarf and control mice (N) males were subjected to visceral fat transplant (VFT) surgery. All procedures were adapted from previously established protocols (Masternak et al ., 2012; Menon et al ., 2014). The animals were anesthetized with ketamine/xylazine and shaved and prepared in a sterile environment.…”

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

“…Visceral fat removal elevated the respiratory quotient in GHRKO mice, but had the opposite effect in WT mice (Masternak et al ., 2012). These observations suggested that WAT derived from long‐lived strains of mice, that is, good‐quality WAT, can increase whole‐body lipid utilization.…”

Long-lived crowded-litter mice exhibit lasting effects on insulin sensitivity and energy homeostasis

“…In particular, reduction of intra-abdominal ("visceral") adipose tissue by surgical removal (24) or as a result of CR (12) is associated with a significant improvement in glucose tolerance in mice. Differences in distribution of adipose tissue could, in principle, influence circulating levels of adipocyte-derived cytokines (adipokines) such as adiponectin and resistin (45), which modulate insulin sensitivity. Thus, it has been suggested that enhanced insulin sensitivity of long-lived GHR-KO mice may be due to the altered secretory profile of visceral fat and, in particular, to enhanced adiponectin secretion by these fat depots (45).…”