The open access paper here makes an interesting companion piece to a recent review of what is known of the role of fat tissue in the longevity of dwarf mouse lineages with disrupted growth hormone signaling. The loss of function in mice is analogous to that found in the small human population that exhibits Laron syndrome. Examination of that population has not yet produce unarguable evidence of any greater life span or resistance to age-related disease. From the evidence to date, we should probably expect favorable adjustments in longevity related to growth hormone and insulin signaling to fall into the broad class of interventions that have much larger effects in short-lived species, such as mice, than in long-lived species, such as our own.
Long-lived mutant mice, such as Ames dwarf, Snell dwarf, and GKO mice, have increased percent body fat and abnormal fat distribution, with preservation of subcutaneous and relatively less visceral fat compared to controls, raising the idea that altered function of adipose tissue within these mice may contribute to their insulin sensitivity, longevity, and disease resistance. To delineate the effects of GH on specific tissues, we evaluated adipose tissue in mice with global disruption of GHR (GKO mice), as well as mice with disruption of GHR in liver (LKO), muscle (MKO), or fat (FKO).
Based on the structure and function of adipocytes and their surrounding stroma, adipose tissue is divided into two categories, white adipose tissue (WAT) and brown adipose tissue (BAT). Its function is to store excess energy in the form of triglycerides for future use. BAT is responsible for dissipating energy in the form of heat through non-shivering thermogenesis. Adipose tissue also influences the activity of macrophages, T cells, B cells, mast cells, dendritic cells, and neutrophils. The inflammatory response of adipose tissue is mainly regulated by macrophages. M1 macrophages produce pro-inflammatory cytokines. In contrast, M2 macrophages are anti-inflammatory and help to maintain tissue homeostasis. In principle, delay or reversal of M1/M2 macrophage polarization might contribute to the insulin sensitivity, disease resistance, and longevity of Ames, Snell, or GKO mice, but no data on this point are yet available.
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 inflammatory cytokines. 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 growth hormone (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.