Dietary fat drives whole-body insulin resistance and promotes intestinal inflammation independent of body weight gain

Abstract Background The obesogenic potential of high-fat diets (HFD) in rodents is attenuated when the protein:carbohydrate ratio is increased. However, it is not known if intake of a HFD irrespective of the protein:carbohydrate ratio and in the absence of weight gain, affects glucose homeostasis and the gut microbiota. Methods We fed C57BL6/J mice 3 different HFDs with decreasing protein:carbohydrate ratios for 8 weeks and compared the results to a LFD reference group. We analyzed the gut microbiota composition by 16S rDNA amplicon sequencing and the intestinal gene expression by real time PCR. Whole body glucose homeostasis was evaluated by insulin- and glucose tolerance tests as well as by hyperinsulinemic euglycemic clamp experiments. Results HFD-fed mice, irrespective of protein:carbohydrate ratio, exhibited impaired glucose tolerance but not insulin tolerance when compared to LFD-fed reference mice. Hyperinsulinemic euglycemic clamp experiments revealed tissue-specific effects on glucose homeostasis in all HFD-fed groups. HFD-fed mice exhibited decreased insulin-stimulated glucose uptake in white but not in brown adipose tissue, and sustained endogenous glucose production under insulin-stimulated conditions. We observed no impairment of insulin-stimulated glucose uptake in skeletal muscles of different fiber type composition. HFD-feeding altered the gut microbiota composition paralleled by increased expression of pro-inflammatory cytokines and genes involved in gluconeogenesis in intestinal epithelial cells in the jejunum. Conclusions Intake of a HFD profoundly affected glucose homeostasis, gut inflammatory responses, and gut microbiota composition in the absence of fat mass accretion.