Endocrine Abstracts

Both type 2 diabetes (T2D) and obesity are the result of a complex interaction between genes and environment, as well as complex interactions between the tissues of the body. The latter include effects of new adipokines released by fat that influence insulin action in other tissues of the body, as well as increasingly complex effects of the brain and adipose tissue on control of metabolism. Mouse models provide a powerful tool to investigate these interactions in disease pathogenesis. These studies have revealed new classes of insulin action and new mechanisms of tissue cross-talk in the pathogenesis of obesity and diabetes, as well as impact of genes, environment and the gut microbiome on disease pathogenesis. For example, we have previously shown that C57BL/6 mice (B6J) are susceptible to diet induced obesity, marked insulin resistance and metabolic syndrome, while 129S1 mice from Jax (here identified as 129J) are resistant to development of obesity and metabolic syndrome. Likewise, when challenged with genetically-induced insulin resistance, more than 90% of B6J mice develop diabetes, while <5% of 129J mice become diabetic. Genome-wide scanning indicates at least one of the genes involved in the difference in insulin resistance is the gene for PKCδ. Recently, we have extended this interaction between genes and environment using a unique experimental paradigm in which we have compared the responses of these two strains of mice from Jax to an almost isogenic strain of 129 mice from Taconic Farms (129T). Interestingly, while the 129J mice are resistant to this high fat diet challenge, 129T mice show a different phenotype, being susceptible to diet-induced obesity, but retaining normal insulin sensitivity. Thus, compared to B6J mice, the 129T mice represent a model of the ‘healthy’ obese. This phenotype however is related to environmental influences. Following ‘normalization’ of the environment by inbreeding these three strains of mice in our animal facility for several generations, the 129T mice lose their susceptibility to diet-induced obesity and became very similar to the obesity resistant 129J mice. Analysis of the composition of gut microbiota reveals profound differences in the relative amounts of bacterial species in the intestine between the three different commercial mouse lines and their environmentally-conditioned equivalents. The composition of the microbiome for each strain uniquely correlate with the genetic background, different diets and different environmental histories, i.e. the provenance, of these mice. These changes in microbiota are also associated with changes in production of the inflammatory mediators by the gut and to the production and secretion of gut hormones known to influence energy intake and metabolic homeostasis. When mice are treated with different antibiotics, the microbiome changes and this is associated with changes in insulin signaling and metabolism. Our study allowed us for the first time to unravel how diet, genetic background, as well as original housing conditions, each independently contribute in shaping the gut flora composition which will drive the susceptibility of mice to diet-induced obesity, which can be reprogrammed by exposing mice to new environmental factors.