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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.

SUBMITTER: Pescador N

PROVIDER: S-EPMC8577482 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Pescador Nuria N Francisco Vera V Vázquez Patricia P Esquinas Eva María EM González-Páramos Cristina C Valdecantos M Pilar MP García-Martínez Irma I Urrutia Andrés A AA Ruiz Laura L Escalona-Garrido Carmen C Foretz Marc M Viollet Benoit B Fernández-Moreno Miguel Ángel MÁ Calle-Pascual Alfonso L AL Obregón María Jesús MJ Aragonés Julián J Valverde Ángela M ÁM

Redox biology 20211019

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- ...[more]

PMID: 34736121

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Project description:ObjectivesThe mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth and metabolism. In mice, activation of mTOR controls cold adaptation by promoting the recruitment and the activation of brown adipose tissue (BAT). DEP-domain containing mTOR-interacting protein (DEPTOR) interacts with mTOR to modulate its activity. Whether DEPTOR levels are modulated by cold in BAT and whether this protein regulates brown adipocyte development and thermogenic activation has never been tested.MethodsDEPTOR levels were measured in mouse tissues upon cold exposure and in brown preadipocytes following the induction of adipogenesis. Lentiviruses expressing short-hairpin RNA were used to repress DEPTOR expression in brown preadipocytes in vitro. Conditional deletion of DEPTOR in brown preadipocytes and in mature brown fat cells was achieved by crossing DEPTOR floxed mice with either Myf5-Cre or Ucp1-CreERT2 mice. These animals were exposed to cold and extensively phenotyped.ResultsDEPTOR is highly expressed in BAT and its levels are induced by chronic cold exposure, a condition that triggers BAT expansion and activation. Supporting a role for DEPTOR in brown fat cell recruitment, we found that DEPTOR is induced during brown adipocyte development and that its depletion impairs adipogenesis in vitro. This adipogenic lesion was associated with defects in both Akt activation and the expression of key adipogenic regulators. Conditional deletion of DEPTOR in brown preadipocytes or mature brown fat cells did not impact BAT recruitment and thermogenesis in mice but slightly reduced the expression of adipogenic and lipogenic genes.ConclusionsDEPTOR is highly expressed in BAT and its levels are dynamically regulated during brown fat cell development and upon cold exposure. Although DEPTOR depletion severely represses brown fat adipogenesis in vitro, its deletion is dispensable for BAT development, recruitment, and thermogenic activation in mice.

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

Publications

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

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