Insulin resistance and obesity are major public health concerns. The impact of diet and genetics on insulin resistance and obesity is well accepted. Additionally, the gut microbiota has been shown to influence obesity and metabolic disorders. However, much remains to be understood about the role of gut microbiota in the development of insulin resistance and obesity. We utilized a mouse model lacking PAS kinase, a protein involved in cellular metabolism, in order to better understand the relationship between diet, genetics and the gut microbiota. Previous research has shown that mice lacking PAS kinase were protected from the effects of a high fat diet, gaining less weight and showing a better response to insulin. Surprisingly, when PAS-kinase deficient mice were placed on a western-style, high fat, high sugar (HFHS) diet, they became obese and had an impaired response to insulin, much like wild type mice on the same diet. Mutant mice did, however, show more resistance to the effects of the unhealthy diet in one aspect-they maintained normal levels of claudin-1 in the colon, suggesting that they were less likely to develop excessive gut permeability (leaky gut). While significant differences in gut microbial composition were seen in response to the HFHS diet, with shifts in the ratio of Firmicutes/Bacteroidetes and increases in the levels of Actinobacteria, none of the differences correlated with genotype. Unexpectedly, however, within the mice on the HFHS diet and regardless of genotype, the composition of the gut microbiota diverged into two clusters. The mice in one cluster showed more resistance to obesity and their glucose response was like that of wild type mice on a healthy normal chow diet (NCD), while mice in the other cluster showed more weight gain and impaired glucose response. No similar gut microbiota divergence occurred in mice on the NCD, suggesting that the HFHS diet made mice vulnerable to (but did not cause) the development of a harmful gut microbiota, whereas the healthy NCD protected against spontaneous harmful shifts in the composition of the gut microbiota.



College and Department

Life Sciences; Microbiology and Molecular Biology



Date Submitted


Document Type



PAS-kinase, gut microbiota, western diet, metabolism, obesity, glucose tolerance



Included in

Life Sciences Commons