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

Metabolism. 2016 Dec;65(12):1706-1719. doi: 10.1016/j.metabol.2016.09.002. Epub 2016 Sep 12.


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.

Keywords: Endogenous glucose production; Feeding behavior; Gut microbiota; Intestinal epithelial cells; Weight stability.

MeSH terms

  • Adipose Tissue, White / metabolism
  • Animals
  • Blood Glucose / metabolism
  • Blood Glucose / physiology
  • Dietary Fats / pharmacology*
  • Glucose Intolerance
  • Homeostasis / drug effects
  • Inflammation / chemically induced*
  • Insulin Resistance*
  • Intestines / microbiology
  • Intestines / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microbiota / drug effects
  • Muscle, Skeletal / metabolism
  • Weight Gain*


  • Blood Glucose
  • Dietary Fats