Section for Integrative Physiology – University of Copenhagen

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

Research output: Contribution to journalJournal article


Benjamin Anderschou Holbech Jensen, Thomas Svava Nielsen, Andreas Mæchel Fritzen, Jacob Bak Holm, Even Fjære, Annette Karen Lundbeck Serup, Kamil Borkowski, Steve Risis, Simone I. Pærregaard, Ida Søgaard, Audrey Angélique G Poupeau, Michelle Poulsen, Tao Ma, Christian Sina, Bente Kiens, Lise Madsen, Karsten Kristiansen, Jonas Thue Treebak

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
Issue number12
Pages (from-to)1706-1719
Number of pages14
StatePublished - 2016

    Research areas

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

ID: 168912053