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Metformin reduces macrophage HIF1α-dependent proinflammatory signaling to restore brown adipocyte function in vitro

Abstract : Therapeutic potential of metformin in obese/diabetic patients has been associated to its ability to combat insulin resistance. However, it remains largely unknown the signaling pathways involved and whether some cell types are particularly relevant for its beneficial effects. M1-activation of macrophages by bacterial lipopolysaccharide (LPS) promotes a paracrine activation of hypoxia-inducible factor-1α (HIF1α) in brown adipocytes which reduces insulin signaling and glucose uptake, as well as β-adrenergic sensitivity. Addition of metformin to M1-polarized macrophages blunted these signs of brown adipocyte dysfunction. At the molecular level, metformin inhibits an inflammatory program executed by HIF1α in macrophages by inducing its degradation through the inhibition of mitochondrial complex I activity, thereby reducing oxygen consumption in a reactive oxygen species (ROS)-independent manner. In obese mice, metformin reduced inflammatory features in brown adipose tissue (BAT) such as macrophage infiltration, proinflammatory signaling and gene expression, and restored the response to cold exposure. In conclusion, the impact of metformin on macrophages by suppressing a HIF1α-dependent proinflammatory program is likely responsible for a secondary beneficial effect on insulin-mediated glucose uptake and β-adrenergic responses in brown adipocytes.
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https://hal.archives-ouvertes.fr/hal-03441515
Contributeur : Marc Foretz Connectez-vous pour contacter le contributeur
Soumis le : mardi 23 novembre 2021 - 10:12:48
Dernière modification le : vendredi 3 décembre 2021 - 03:09:51

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DOI 10.1016:j.redox.2021.1021...
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Nuria Pescador, Vera Francisco, Patricia Vázquez, Eva María Esquinas, Cristina González-Páramos, et al.. Metformin reduces macrophage HIF1α-dependent proinflammatory signaling to restore brown adipocyte function in vitro. Redox Biology, Elsevier, 2021, 48, pp.102171. ⟨10.1016/j.redox.2021.102171⟩. ⟨hal-03441515⟩

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