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Pan-AMPK activator O304 prevents gene expression changes and remobilisation of histone marks in islets of diet-induced obese mice
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
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2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 24410Article in journal (Refereed) Published
Abstract [en]

AMP-activated protein kinase (AMPK) has an important role in cellular energy homeostasis and has emerged as a promising target for treatment of Type 2 Diabetes (T2D) due to its beneficial effects on insulin sensitivity and glucose homeostasis. O304 is a pan-AMPK activator that has been shown to improve glucose homeostasis in both mouse models of diabetes and in human T2D subjects. Here, we describe the genome-wide transcriptional profile and chromatin landscape of pancreatic islets following O304 treatment of mice fed high-fat diet (HFD). O304 largely prevented genome-wide gene expression changes associated with HFD feeding in CBA mice and these changes were associated with remodelling of active and repressive chromatin marks. In particular, the increased expression of the β-cell stress marker Aldh1a3 in islets from HFD-mice is completely abrogated following O304 treatment, which is accompanied by loss of active chromatin marks in the promoter as well as distant non-coding regions upstream of the Aldh1a3 gene. Moreover, O304 treatment restored dysfunctional glucose homeostasis as well as expression of key markers associated with β-cell function in mice with already established obesity. Our findings provide preclinical evidence that O304 is a promising therapeutic compound not only for T2D remission but also for restoration of β-cell function following remission of T2D diabetes.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021. Vol. 11, no 1, article id 24410
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-190971DOI: 10.1038/s41598-021-03567-3ISI: 000734163400004PubMedID: 34949756Scopus ID: 2-s2.0-85121738771OAI: oai:DiVA.org:umu-190971DiVA, id: diva2:1624632
Funder
Knut and Alice Wallenberg Foundation, 2015.0278Swedish Research Council, 2018-05973The Kempe Foundations, SMK-1863Available from: 2022-01-04 Created: 2022-01-04 Last updated: 2022-09-15Bibliographically approved

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López-Pérez, Ana R.Norlin, StefanSteneberg, PärRemeseiro, SilviaEdlund, HelenaHörnblad, Andreas

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López-Pérez, Ana R.Norlin, StefanSteneberg, PärRemeseiro, SilviaEdlund, HelenaHörnblad, Andreas
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Umeå Centre for Molecular Medicine (UCMM)Wallenberg Centre for Molecular Medicine at Umeå University (WCMM)
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