Effects of insulin gene dosage on murine obesity and lifespan

There are numerous parallels between aging and obesity, and insulin may play a crucial role in modulating both conditions. For instance, elevated insulin levels are closely associated with obesity, although the causal role of insulin hypersecretion in the development of obesity remains controversial. Interestingly, genetically reducing components of insulin/insulin-like growth factor (IGF)-1 signaling can increase lifespan in invertebrates and mammals. However, impaired insulin-stimulated glucose disposal is a form of decreased insulin signaling that is paradoxically a detrimental feature of mammalian aging, whereas long-living mammals often show enhanced responsiveness to insulin stimulation. Therefore, the role of insulin/IGF-1 signaling for mammalian longevity, and the relative functions of the insulin and IGF-1 ligands, are still unclear. The lifelong effects of moderately decreasing insulin production in mammals had not been directly tested. In this dissertation, the goal was to further delineate effects of lowering insulin levels on obesity and metabolic health across the lifespan of a mammalian model organism, culminating in an evaluation of longevity. We used a model in which the rodent-specific insulin gene was fully inactivated (Ins1-null), and compared mice with full or partial expression of the ancestral insulin gene (Ins2). Male and female Ins1-/-:Ins2+/- and Ins1-/-:Ins2+/+ littermates were fed a chow diet or high fat diet, and were evaluated across their lifetime to determine long-term effects of reducing insulin gene dosage on obesity, glucose homeostasis, and other physiological parameters. The studies herein show that murine insulin levels and metabolic homeostasis might be regulated in a sex-specific, environmentally-dependent manner, since inactivating one Ins2 allele unexpectedly did not cause a consistent reduction of circulating insulin in Ins1-null male mice, and we observed cross-cohort hyper-variability in circulating insulin of male mice. However, limiting insulin hypersecretion in young, growing female mice can confer long-term protection against obesity. Furthermore, we found that lowering circulating insulin has the potential to improve glucose homeostasis and insulin sensitivity in advanced age, as well as lead to lifespan extension in mammals. To our knowledge, these studies are the first to demonstrate that a targeted, moderate reduction of insulin may be sufficient to promote healthier aging and extend lifespan in mammals.Medicine, Faculty ofGraduat