Dietary fat drives whole-body insulin resistance and promotes intestinal inflammation independent of body weight gain.
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.
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark. Electronic address: benjamin.jensen@bio.ku.dk.
Benjamin A H
BA
Jensen
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Thomas S
TS
Nielsen
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Andreas M
AM
Fritzen
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Jacob B
JB
Holm
National Institute of Nutrition and Seafood Research, Bergen, Norway.
Even
E
Fjære
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Annette K
AK
Serup
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Kamil
K
Borkowski
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Steve
S
Risis
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Simone I
SI
Pærregaard
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Ida
I
Søgaard
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Audrey
A
Poupeau
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Michelle
M
Poulsen
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Tao
T
Ma
Medical Department, University Hospital Schleswig-Holstein, Campus Lübeck, Germany.
Christian
C
Sina
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Bente
B
Kiens
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark; National Institute of Nutrition and Seafood Research, Bergen, Norway.
Lise
L
Madsen
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark; BGI-Shenzhen, Shenzhen, China. Electronic address: kk@bio.ku.dk.
Karsten
K
Kristiansen
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: jttreebak@sund.ku.dk.
Jonas T
JT
Treebak
D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism / Q000502:physiology; D004041:Dietary Fats / Q000494:pharmacology*; D018149:Glucose Intolerance; D006706:Homeostasis / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced*; D007333:Insulin Resistance; D007422:Intestines / Q000382:microbiology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000187:drug effects; D018482:Muscle, Skeletal / Q000378:metabolism; D015430:Weight Gain
D001786:Blood Glucose; D004041:Dietary Fats
Endogenous glucose production; Feeding behavior; Gut microbiota; Intestinal epithelial cells; Weight stability