Arctic berry extracts target the gut–liver axis to alleviate metabolic endotoxaemia, insulin resistance and hepatic steatosis in diet-induced obese mice
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There is growing evidence that fruit polyphenols exert beneficial effects on the metabolic syndrome, but the underlying mechanisms remain poorly understood. In the present study, we aimed to analyse the effects of polyphenolic extracts from five types of Arctic berries in a model of diet-induced obesity.
Male C57BL/6 J mice were fed a high-fat/high-sucrose (HFHS) diet and orally treated with extracts of bog blueberry (BBE), cloudberry (CLE), crowberry (CRE), alpine bearberry (ABE), lingonberry (LGE) or vehicle (HFHS) for 8 weeks. An additional group of standard-chow-fed, vehicle-treated mice was included as a reference control for diet-induced obesity. OGTTs and insulin tolerance tests were conducted, and both plasma insulin and C-peptide were assessed throughout the OGTT. Quantitative PCR, western blot analysis and ELISAs were used to assess enterohepatic immunometabolic features. Faecal DNA was extracted and 16S rRNA gene-based analysis was used to profile the gut microbiota.
Treatment with CLE, ABE and LGE, but not with BBE or CRE, prevented both fasting hyperinsulinaemia (mean ± SEM [pmol/l]: chow 67.2 ± 12.3, HFHS 153.9 ± 19.3, BBE 114.4 ± 14.3, CLE 82.5 ± 13.0, CRE 152.3 ± 24.4, ABE 90.6 ± 18.0, LGE 95.4 ± 10.5) and postprandial hyperinsulinaemia (mean ± SEM AUC [pmol/l × min]: chow 14.3 ± 1.4, HFHS 31.4 ± 3.1, BBE 27.2 ± 4.0, CLE 17.7 ± 2.2, CRE 32.6 ± 6.3, ABE 22.7 ± 18.0, LGE 23.9 ± 2.5). None of the berry extracts affected C-peptide levels or body weight gain. Levels of hepatic serine phosphorylated Akt were 1.6-, 1.5- and 1.2-fold higher with CLE, ABE and LGE treatment, respectively, and hepatic carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-1 tyrosine phosphorylation was 0.6-, 0.7- and 0.9-fold increased in these mice vs vehicle-treated, HFHS-fed mice. These changes were associated with reduced liver triacylglycerol deposition, lower circulating endotoxins, alleviated hepatic and intestinal inflammation, and major gut microbial alterations (e.g. bloom of Akkermansia muciniphila, Turicibacter and Oscillibacter) in CLE-, ABE- and LGE-treated mice.
Our findings reveal novel mechanisms by which polyphenolic extracts from ABE, LGE and especially CLE target the gut–liver axis to protect diet-induced obese mice against metabolic endotoxaemia, insulin resistance and hepatic steatosis, which importantly improves hepatic insulin clearance. These results support the potential benefits of these Arctic berries and their integration into health programmes to help attenuate obesity-related chronic inflammation and metabolic disorders.
All raw sequences have been deposited in the public European Nucleotide Archive server under accession number PRJEB19783 (https://www.ebi.ac.uk/ena/data/view/PRJEB19783).
KeywordsAkkermansia muciniphila Arctic berries CEACAM-1 Gut microbiota Insulin clearance
Alpine bearberry extract
Bog blueberry extract
Branched-chain amino acids
Carcinoembryonic antigen-related cell adhesion molecule 1
i.p. insulin tolerance test
Kyoto Encyclopedia of Genes and Genomes
Short-chain fatty acids
We are grateful to V. Dumais, C. Dion, C. Dallaire and J. Dupont-Morissette (Québec Heart and Lung Institute, Laval University, Canada) for their expert assistance with animal experiments and to P. Feutry and P. Dubé (Institute of Nutrition and Functional Foods, Laval University, Canada) for their technical support with GC-FID analysis. We dedicate this work to the memory of Dr Éric Dewailly, who was an authority on environmental and human health in the circumpolar world, an exceptional mentor to M. Lemire, M. Lucas and C. S. Harris, and a brilliant mind.
This work was supported by funding from ArcticNet (2011–2015) to ED and from the Canadian Institutes of Health Research (CIHR; FDN-143247), JA DeSève Foundation and Sentinel North to AM.
Duality of interest
AM has been the holder of Pfizer/CIHR partnered research chair. AM and YD have received grants from Nutra Canada. MLe and CSH have received grants from the Kativik Regional Government. None of these funding sources are relevant to this publication. This work was approved by the Nunavik Nutrition and Health Committee. No other potential dualities of interest are associated with this article.
This study was conceived by AM, MLe, MLu and CSH, and designed by FFA, AM and GP. FFA, TV, MLe and SD performed the experiments. All authors were involved in the analysis and discussion of the data. FFA wrote the manuscript. All authors reviewed and approved the final manuscript. AM and FFA are responsible for the integrity of the work as a whole.