TY - JOUR

T1 - Dietary fat drives whole-body insulin resistance and promotes intestinal inflammation independent of body weight gain

AU - Jensen, Benjamin Anderschou Holbech

AU - Nielsen, Thomas Svava

AU - Fritzen, Andreas Mæchel

AU - Holm, Jacob Bak

AU - Fjære, Even

AU - Serup, Annette Karen Lundbeck

AU - Borkowski, Kamil

AU - Risis, Steve

AU - Pærregaard, Simone I.

AU - Søgaard, Ida

AU - Poupeau, Audrey Angélique G

AU - Poulsen, Michelle

AU - Ma, Tao

AU - Sina, Christian

AU - Kiens, Bente

AU - Madsen, Lise

AU - Kristiansen, Karsten

AU - Treebak, Jonas Thue

N1 - CURIS 2016 NEXS 325

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Faculty of Science

KW - Intestinal epithelial cells

KW - Weight stability

KW - Gut microbiota

KW - Feeding behavior

KW - Endogenous glucose production

U2 - 10.1016/j.metabol.2016.09.002

DO - 10.1016/j.metabol.2016.09.002

M3 - Journal article

C2 - 27832859

VL - 65

SP - 1706

EP - 1719

JO - Metabolism

JF - Metabolism

SN - 0026-0495

IS - 12

ER -