Muscle-dependent regulation of adipose tissue function in long-lived growth hormone-mutant mice

Altered adipose tissue may contribute to the longevity of Snell dwarf and growth hormone receptor (GHR) knock-out mice. We report here that white (WAT) and brown (BAT) fat have elevated UCP1 in both kinds of mice, and that adipocytes in WAT depots turn beige/brown. These imply increased thermogenesis and are expected to lead to improved glucose control. Both kinds of long-lived mice show lower levels of inflammatory M1 macrophages and higher levels of anti-inflammatory M2 macrophages in BAT and WAT, with correspondingly lower levels of TNFα, IL-6, and MCP1. Experiments with mice with tissue-specific disruption of GHR showed that these adipocyte and macrophage changes were not due to hepatic IGF1 production nor to direct GH effects on adipocytes, but instead reflect GH effects on muscle. Muscles deprived of GH signals, either globally (GKO) or in muscle only (MKO), produce higher levels of circulating irisin and its precursor FNDC5. The data thus suggest that the changes in adipose tissue differentiation and inflammatory status seen in long-lived mutant mice reflect interruption of GH-dependent irisin inhibition, with consequential effects on metabolism and thermogenesis.