Global metabolite profiling of mice with high-fat diet-induced obesity chronically treated with AMPK activators R118 or metformin reveals tissue-selective alterations in metabolic pathways

BMC Research Notes

Yasumichi Hitoshi¹  Donald G Payan¹  Rajinder Singh¹  Luke Boralsky¹  Simon J Shaw¹  Dane A Goff¹  Lisa Gross¹  Gerald Uy¹  Vadim Markovtsov¹  Yingwu Li¹  Tian-Qiang Sun¹  Yonchu Jenkins¹ 

[1] Rigel Pharmaceuticals, Inc., South San Francisco, CA, USA

关键词: Diet-induced obese mice;    Small molecule;    Metabolism;    Skeletal muscle;    Metabolomics;    Diabetes;    Mitochondria;    Complex I;    Metformin;    AMPK;   

Others  :  1127421
DOI  :  10.1186/1756-0500-7-674

 received in 2014-06-18, accepted in 2014-09-17,  发布年份 2014

【 摘 要 】

Background

The novel small molecule R118 and the biguanide metformin, a first-line therapy for type 2 diabetes (T2D), both activate the critical cellular energy sensor 5′-AMP-activated protein kinase (AMPK) via modulation of mitochondrial complex I activity. Activation of AMPK results in both acute responses and chronic adaptations, which serve to restore energy homeostasis. Metformin is thought to elicit its beneficial effects on maintenance of glucose homeostasis primarily though impacting glucose and fat metabolism in the liver. Given the commonalities in their mechanisms of action and that R118 also improves glucose homeostasis in a murine model of T2D, the effects of both R118 and metformin on metabolic pathways in vivo were compared in order to determine whether R118 elicits its beneficial effects through similar mechanisms.

Results

Global metabolite profiling of tissues and plasma from mice with diet-induced obesity chronically treated with either R118 or metformin revealed tissue-selective effects of each compound. Whereas metformin treatment resulted in stronger reductions in glucose and lipid metabolites in the liver compared to R118, upregulation of skeletal muscle glycolysis and lipolysis was apparent only in skeletal muscle from R118-treated animals. Both compounds increased β-hydroxybutyrate levels, but this effect was lost after compound washout. Metformin, but not R118, increased plasma levels of metabolites involved in purine metabolism.

Conclusions

R118 treatment but not metformin resulted in increased glycolysis and lipolysis in skeletal muscle. In contrast, metformin had a greater impact than R118 on glucose and fat metabolism in liver tissue.

【 授权许可】

   
2014 Jenkins et al.; licensee BioMed Central Ltd.

【 图 表 】

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