Per-arnt-sim (PAS) kinase is a nutrient sensing serine/threonine kinase whose absence protects against triglyceride accumulation, insulin resistance, a decreased metabolic rate and increased weight gain in response to a high fat diet, using phenotypes associated with the gut microbiome. Herein we further explored the metabolic effects of PAS kinase-deficiency(PASK?/?) on a high fat high sugar (HFHS) diet, including contributions from an altered microbiome. PASK?/? mice were not protected from weight gain on the HFHS diet but were resistant to liver triglyceride accumulation. Microbiome analysis of both WT and PASK?/? mice revealed a forked shift with two discrete clusters of HFHS-fed mice emerging, which displayed increased beta and decreased alpha diversity compared with the normal chow diet (NCD). A “lower” cluster associated with both increased weight gain and glucose intolerance contained elevated levels of Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria and Defferibacteres. Lower cluster PASK?/? mice also influenced glucose tolerance and Claudin-1 expression, a protein associated with leaky gut. These results suggest PAS kinase-deficiency can protect mice against the deleterious effects of liver triglyceride accumulation, leaky gut and glucose intolerance in response to diet; however, microbiome imbalance can override protection. In addition, these results support a healthy diet and suggest microbial culprits associated with metabolic disease.
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