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Azoxystrobin,a mitochondrial complex III Qo site inhibitor,exerts beneficial metabolic effects in vivo and in vitro
Authors:An-Hui Gao  Yan-Yun Fu  Kun-Zhi Zhang  Mei Zhang  Hao-Wen Jiang  Li-Xia Fan  Fa-Jun Nan  Chong-Gang Yuan  Jia Li  Yu-Bo Zhou  Jing-Ya Li
Institution:1. Laboratory of Physiology, School of Life Science, East China Normal University, Shanghai 200062, China;2. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Abstract:

Background

Several anti-diabetes drugs exert beneficial effects against metabolic syndrome by inhibiting mitochondrial function. Although much progress has been made toward understanding the role of mitochondrial function inhibitors in treating metabolic diseases, the potential effects of these inhibitors on mitochondrial respiratory chain complex III remain unclear.

Methods

We investigated the metabolic effects of azoxystrobin (AZOX), a Qo inhibitor of complex III, in a high-fat diet-fed mouse model with insulin resistance in order to elucidate the mechanism by which AZOX improves glucose and lipid metabolism at the metabolic cellular level.

Results

Acute administration of AZOX in mice increased the respiratory exchange ratio. Chronic treatment with AZOX reduced body weight and significantly improved glucose tolerance and insulin sensitivity in high-fat diet-fed mice. AZOX treatment resulted in decreased triacylglycerol accumulation and down-regulated the expression of genes involved in liver lipogenesis. AZOX increased glucose uptake in L6 myotubes and 3T3-L1 adipocytes and inhibited de novo lipogenesis in HepG2 cells. The findings indicate that AZOX-mediated alterations to lipid and glucose metabolism may depend on AMP-activated protein kinase (AMPK) signaling.

Conclusions

AZOX, a Qo inhibitor of mitochondrial respiratory complex III, exerts whole-body beneficial effects on the regulation of glucose and lipid homeostasis in high-fat diet-fed mice.

General significance

These findings provide evidence that a Qo inhibitor of mitochondrial respiratory complex III could represent a novel approach for the treatment of obesity.
Keywords:Azoxystrobin  Mitochondria complex III  Metabolic diseases  AMP-activated protein kinase
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