title: The role of metformin and resveratrol in the prevention of hypoxia-inducible factor 1α accumulation and fibrosis in hypoxic adipose tissue.
abstract: Hypoxic activation of hypoxia-inducible factor 1α (HIF-1α) 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-1α 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-1α 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-1α accumulation with dephosphorylation of inositol-requiring enzyme 1α and eukaryotic initiation factor 2α, indicative of suppression of hypoxic HIF-1α activation and endoplasmic reticulum stress. Metformin and resveratrol down-regulated gene expressions of Col3α, Col6α, elastin and lysyl oxidase and thereby reduced collagen deposition in adipose tissue. The increased gene expressions of TNF-α, 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-1α 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-1α activation-induced fibrosis and inflammation in adipose tissue, although by different mechanisms.
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Xiaole
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Aiyun
authors.initials: A
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors.forename: Lian-Wen
authors.initials: LW
authors.lastname: Qi
authors.affiliation: State Key Laboratory of Natural Medicines, Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TMAC-CM, China Pharmaceutical University, Nanjing, China.
authors.forename: Junping
authors.initials: J
authors.lastname: Kou
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Baolin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000378:metabolism / Q000517:prevention & control; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013267:Stilbenes; D008687:Metformin; D000077185:Resveratrol