Details

Autor(en) / Beteiligte

• Pescador, Nuria
• Francisco, Vera
• Vázquez, Patricia
• Esquinas, Eva María
• González-Páramos, Cristina
• Valdecantos, M. Pilar
• García-Martínez, Irma
• Urrutia, Andrés A.
• Ruiz, Laura
• Escalona-Garrido, Carmen
• Foretz, Marc
• Viollet, Benoit
• Fernández-Moreno, Miguel Ángel
• Calle-Pascual, Alfonso L.
• Obregón, María Jesús
• Aragonés, Julián
• Valverde, Ángela M.

Titel

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

Ist Teil von

• Redox biology, 2021-12, Vol.48, p.102171-102171, Article 102171

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2021

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. [Display omitted] •Macrophage-mediated inflammation in brown adipocytes stabilizes HIF1α.•Stabilization of HIF1α reduces brown adipocyte hormonal responses.•Metformin attenuates inflammation and BAT dysfunction in obese mice.•Mitochondrial complex I inhibition by metformin reduces HIF1α in macrophages.•Targeting macrophages HIF1α by metformin alleviates brown adipocyte inflammation.