A few varieties of dwarf mice exhibit considerable longevity. They are produced via forms of mutation that disable portions of growth hormone metabolism, such as via growth hormone receptor knockout. Most research has thus focused on insulin signaling, IGF-1, and other pathways closely tied to growth hormone. Here, scientists instead focus on the behavior of fat tissue in these long-lived mouse lineages, suggesting that the significant differences they observe in the metabolism of visceral fat may contribute to the impact on aging.
It is well known that visceral fat is metabolically active, and excess amounts create chronic inflammation through a number of mechanisms, including accelerated generation of senescent cells. That doesn’t appear to happen to anywhere near the same degree in dwarf mice, and the researchers offer their thoughts as to why this might be the case. In this context, it would be interesting to compare the biochemistry of the small human population exhibiting Laron syndrome, which similarly results from a loss of function mutation affecting growth hormone metabolism. They do not appear to live any longer than the rest of us, but there are suggestions in the data that they may be modestly more resistant to some age-related conditions.
Dwarf mice were found to have functionally altered adipose tissues. Generally, three types of adipose tissue are found in mammals: white, brown, and beige. White adipose tissue (WAT) is considered the body’s energy storage for times of energy scarcity while brown adipose tissue (BAT) is a unique, major energy consuming, heat producing organ. This highly thermogenic BAT, found commonly in small sized mammals and juveniles of larger-bodied mammals including humans, is very important for physiology in general and metabolic homeostasis in particular. It not only maintains endothermy but also is crucial for many physiological processes relating to decreased metabolic rate. Lastly, beige adipose is originally derived from WAT precursors but has properties more similar to BAT.
For decades, both WAT and BAT were largely excluded from evolutionary and developmental research in cell and tissue biology. Due to the common notion that adipose tissue was mainly assigned a passive role for lipid storage, insulation, and mechanical buffering it was considered a large source of unwanted biological variance due to individual feeding status and other environmental factors driving the extent and composition of WAT and BAT. More recently, WAT has been recognized as a major endocrine organ, and as such, the interest in adipose tissues has increased dramatically.
Interestingly, there seem to be peculiarities in WAT localization in homozygous long-lived Ames dwarf (AD) mice compared to normal sized, heterozygous controls. The potential differences in WAT depots compared to other laboratory mice became most visible when AD were exposed to a high fat diet containing 60% fat. Diet-induced obesity in AD seemingly did not lead to expected metabolic derangements which clearly developed in littermate controls, despite significant increases in the amount of their subcutaneous and visceral depots. Instead, “obese” AD mice remained insulin sensitive and showed normal levels of adiponectin. The adipokine adiponectin, acts as an important anti-inflammatory factor and usually correlates positively with the retention of insulin sensitivity.
We thus hypothesize here that growth hormone deficient, genetically dwarf mice, such as Ames dwarf and Snell dwarf, have a metabolic advantage when kept on high-fat diets through the storing of triglycerides preferentially in subcutaneous depots as opposed to evoking depots around the visceral organs like many common laboratory mouse models. This is important as visceral WAT is primarily associated with metabolic complications such as insulin resistance, increased inflammation, and even cancer, which have detrimental effects on tissue health and metabolism. To date, no adverse metabolic effects are described from expansion of subcutaneous WAT. Rather subcutaneous WAT has been assigned metabolic beneficial roles through its browning ability.