The role of metformin and resveratrol in the prevention of hypoxia-inducible factor 1? accumulation and fibrosis in hypoxic adipose tissue.
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ABSTRACT: Hypoxic activation of hypoxia-inducible factor 1? (HIF-1?) and fibrosis in adipose tissue contribute to adipose dysfunction. This study was designed to investigate the effects of metformin and resveratrol on the regulation of HIF-1? and fibrosis in hypoxic adipose tissue.Mice were fed a high-fat diet to induce hypoxia and fibrosis in adipose tissue; adipose tissue incubated in vitro in 1% O2 showed a similar change. The effects of metformin and resveratrol on hypoxia, HIF-1? accumulation, endoplasmic reticulum stress and gene expressions of extracellular matrix components and pro-inflammatory cytokines were examined.Oral administration of metformin or resveratrol prevented hypoxia and reduced HIF-1? accumulation with dephosphorylation of inositol-requiring enzyme 1? and eukaryotic initiation factor 2?, indicative of suppression of hypoxic HIF-1? activation and endoplasmic reticulum stress. Metformin and resveratrol down-regulated gene expressions of Col3?, Col6?, elastin and lysyl oxidase and thereby reduced collagen deposition in adipose tissue. The increased gene expressions of TNF-?, IL-6, monocyte chemoattractant protein 1 and F4/80 were also down-regulated by metformin and resveratrol. Metformin and resveratrol had similar effects in adipose tissue exposed to 1% O2 . Metformin reduced ATP production and prevented the reduction in oxygen tension in 3T3-L1 cells, suggesting that it prevented hypoxia by limiting oxygen consumption, whereas resveratrol reduced HIF-1? accumulation by promoting its proteasomal degradation via the regulation of AMPK/SIRT1.Hypoxia and fibrosis are early causes of adipose dysfunction in obesity. Both metformin and resveratrol effectively inhibited HIF-1? activation-induced fibrosis and inflammation in adipose tissue, although by different mechanisms.
SUBMITTER: Li X
PROVIDER: S-EPMC4882491 | biostudies-other | 2016 Jun
REPOSITORIES: biostudies-other
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