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The role of metformin and resveratrol in the prevention of hypoxia-inducible
factor 1? accumulation and fibrosis in hypoxic adipose tissue
#MMPMID27059094
Li X
; Li J
; Wang L
; Li A
; Qiu Z
; Qi LW
; Kou J
; Liu K
; Liu B
; Huang F
Br J Pharmacol
2016[Jun]; 173
(12
): 2001-15
PMID27059094
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BACKGROUND AND PURPOSE: 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. EXPERIMENTAL
APPROACH: 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. KEY RESULTS: 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.
CONCLUSION AND IMPLICATIONS: 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.
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