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.

Modulation of hypothalamic AMPK phosphorylation by olanzapine controls energy balance and body weight

“…Thus, metformin might regulate the feeding behavior by modulation of several appetite regulatory pathways. Additionally, oral metformin administration increases BAT UCP-1 levels in obese mice, as we recently reported [77]. Overall, our results point that OLA administration via i.p.…”

Metformin suppresses foam cell formation, inflammation and ferroptosis via the AMPK/ERK signaling pathway in ox‑LDL‑induced THP‑1 monocytes

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Network Pharmacology Analysis and Experimental Validation to Investigate the Mechanism of Total Flavonoids of Rhizoma Drynariae in Treating Rheumatoid Arthritis

“… 49 The activation of the NF-κB pathway can promote transcription and synthesis of multiple inflammation-related mediators, including IL-6 and HIF-1α. 50 HIF-1α can stimulate the transcription and synthesis of VEGF through the HIF signaling pathway, which is one of important mechanisms of synovial neovascularization. 50 …”

“… 50 HIF-1α can stimulate the transcription and synthesis of VEGF through the HIF signaling pathway, which is one of important mechanisms of synovial neovascularization. 50 …”