Abstract
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.
Highlights
In healthy individuals, increased blood glucose levels trigger beta cells in the pancreas to produce insulin
Per-Arnt-Sim kinase-deficient mice(PASK−/−) were previously reported to be resistant to weight gain, adiposity, liver triglyceride accumulation and insulin resistance when placed on a high-fat diet
Male PASK-deficient mice were previously reported as resistant to weight gain, liver triglyceride accumulation and insulin resistance when placed on a high-fat diet [31]
Summary
In healthy individuals, increased blood glucose levels trigger beta cells in the pancreas to produce insulin. Extracellular insulin can subsequently bind to insulin receptors on cellular membranes [1], allowing for increased glucose uptake by the cell by translocating glucose receptors to the cellular membrane, and stimulating glycogen synthesis [2]. A decrease in the cell’s sensitivity to insulin is known as insulin resistance, and it can lead to hyperglycemia, hepatic lipid synthesis and adiposity [3]. The severity of insulin resistance is used to classify individuals as either prediabetic or type 2 diabetic, with prediabetes affecting 33.9% and diabetes affecting 10.5% of adults in the United States [4]. Of adults diagnosed with diabetes, 87.5% were overweight or obese [5], with obesity affecting 39.8% of US adults. Diet plays an important role in the development of obesity and insulin resistance
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