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 -