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

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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 an 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 8weeks 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 a hyperinsulinemic euglycemic clamp experiment.

RESULTS: Compared with LFD-fed reference mice, HFD-fed mice, irrespective of protein:carbohydrate ratio, exhibited impaired glucose tolerance, whereas no differences were observed during insulin tolerance tests. The hyperinsulinemic euglycemic clamp 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 of 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.

Original languageEnglish
JournalMetabolism
Volume65
Issue number12
Pages (from-to)1706-1719
Number of pages14
ISSN0026-0495
DOIs
Publication statusPublished - 2016

    Research areas

  • Faculty of Science - Intestinal epithelial cells, Weight stability, Gut microbiota, Feeding behavior, Endogenous glucose production

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