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

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• 作者：Benjamin A.H. Jensen^a ; ^{benjamin.jensen@bio.ku.dk" class="auth_mail" title="E-mail the corresponding author} ; Thomas S. Nielsen^b ; Andreas M. Fritzen^c ; Jacob B. Holm^a ; Even Fjæ ; re^d ; Annette K. Serup^c ; Kamil Borkowski^a ; Steve Risis^b ; Simone I. Pæ ; rregaard^a ; Ida Sø ; gaard^a ; Audrey Poupeau^b ; Michelle Poulsen^a ; Tao Ma^a ; Christian Sina^e ; Bente Kiens^c ; Lise Madsen^a ; ^d ; Karsten Kristiansen^a ; ^f ; ^{kk@bio.ku.dk" class="auth_mail" title="E-mail the corresponding author} ; Jonas T. Treebak^b ; ^{jttreebak@sund.ku.dk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Intestinal epithelial cells ; Weight stability ; Gut microbiota ; Feeding behavior ; Endogenous glucose production
• 刊名：Metabolism
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：65
• 期：12
• 页码：1706-1719
• 全文大小：1631 K

文摘

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 8 weeks 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.