AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

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Title: AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin
Authors: Börgeson, EmmaWallenius, VilleSyed, Gulam H.Godson, Catherineet al.
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Date: Apr-2017
Online since: 2018-03-21T13:25:12Z
Abstract: Aims/hypothesis: In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo. Methods: Six-week-old male C57BL/6J wild-type and Adipoq −/− mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12 weeks and given vehicle or AICAR (500 μg/g) three times/week from weeks 4–12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35–50 kg/m2) individuals were incubated with vehicle or AICAR (1 mmol/l) for 6 h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry. Results: AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8+ T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p < 0.05), urinary H2O2 (p < 0.05) and renal superoxide levels (p < 0.01) in both wild-type and Adipoq −/− mice. AICAR-mediated protection occurred independently of adiponectin, as similar protection was observed in wild-type and Adipoq −/− mice. In addition, AICAR promoted an M1-to-M2 macrophage phenotype switch and reduced TNF-α production in tissue explants from obese human patients.Conclusions/interpretation: AICAR may promote metabolic health and protect against obesity-induced systemic diseases in an adiponectin-independent manner. Furthermore, AICAR reduced inflammation in human adipose tissue explants, suggesting by proof-of-principle that the drug may reduce obesity-induced complications in humans.
Funding Details: Science Foundation Ireland
metadata.dc.description.othersponsorship: Swedish Research Council
Swedish Society for Medical Research
Åke Wiberg’s Foundation
Konrad and Helfrid Johansson’s Foundation
Wallenberg Centre for Molecular and Translational Medicine
Western Region of Sweden
Erik & Lily Philipson memorial foundation
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type of material: Journal Article
Publisher: Springer
Journal: Diabetologica
Volume: 60
Issue: 4
Start page: 729
End page: 739
Copyright (published version): 2017 the Authors
Keywords: AdiponectinAICARInflammationKidney diseaseLiver diseaseMacrophagesObseity
DOI: 10.1007/s00125-017-4211-9
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
Medicine Research Collection

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