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J Nutr Biochem. 2018 Apr;54:66-76. doi: 10.1016/j.jnutbio.2017.09.026. Epub 2017 Oct 18.

Age-dependent alterations of glucose clearance and homeostasis are temporally separated and modulated by dietary fat.

Author information

1
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Denmark.
2
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
3
Department of Biostatistics and Computational Biology, Dana-Faber Cancer Institute, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
4
Institute of Nutritional Medicine and Medical Department 1, University of Lübeck, Germany.
5
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Denmark; Institute of Metagenomics, BGI-Shenzhen, Shenzhen, China. Electronic address: kk@bio.ku.dk.
6
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Denmark. Electronic address: Benjamin.jensen@bio.ku.dk.

Abstract

Diet- and age-dependent changes in glucose regulation in mice occur, but the temporal development, mechanisms and influence of dietary fat source remain to be defined. We followed metabolic changes in three groups of mice including a low-fat diet (LFD) reference group and two high-fat, high-sucrose diets based on either fish oil (FOD) or soybean oil (SOD), rich in ω3- and ω6-polyunsaturated fatty acids, respectively, to closely monitor the age-dependent development in glucose regulation in both obese (SOD-fed) and lean (LFD- and FOD-fed) mice. We assessed glucose homeostasis and glucose clearance at week 8, 12, 16, 24, 31, and 39 and performed an insulin tolerance test at week 40. We further analyzed correlations between the gut microbiota and key metabolic parameters. Interestingly, alterations in glucose homeostasis and glucose clearance were temporally separated, while 16S ribosomal gene amplicon sequencing revealed that gut microbial alterations formed correlation clusters with fat mass and either glucose homeostasis or glucose clearance, but rarely both. Importantly, effective glucose clearance was maintained in FOD- and even increased in LFD-fed mice, whereas SOD-fed mice rapidly developed impaired glucose clearance followed by a gradual improvement from week 8 to week 39. All groups had similar responses to insulin 40 weeks post diet initiation despite severe nonalcoholic steatohepatitis in SOD-fed mice. We conclude that age-related alterations in glucose regulation may occur in both lean and obese mice and are modulated by dietary fat as indicated by the sustained metabolic homeostasis observed in mice fed ω3-polyunsaturated fatty acids.

KEYWORDS:

Aging; Glucose regulation; Gut microbiota; High-fat diet; Inflammation; Insulin resistance; Obesity

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