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Novel small-molecule PGC-1? transcriptional regulator with beneficial effects on diabetic db/db mice.


ABSTRACT: Peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) has been shown to influence energy metabolism. Hence, we explored a strategy to target PGC-1? expression to treat metabolic syndromes. We developed a high-throughput screening assay that uses the human PGC-1? promoter to drive expression of luciferase. The effects of lead compound stimulation on PGC-1? expression in muscle cells and hepatocytes were investigated in vitro and in vivo. A novel small molecule, ZLN005, led to changes in PGC-1? mRNA levels, glucose uptake, and fatty acid oxidation in L6 myotubes. Activation of AMP-activated protein kinase was involved in the induction of PGC-1? expression. In diabetic db/db mice, chronic administration of ZLN005 increased PGC-1? and downstream gene transcription in skeletal muscle, whereas hepatic PGC-1? and gluconeogenesis genes were reduced. ZLN005 increased fat oxidation and improved the glucose tolerance, pyruvate tolerance, and insulin sensitivity of diabetic db/db mice. Hyperglycemia and dyslipidemia also were ameliorated after treatment with ZLN005. Our results demonstrated that a novel small molecule selectively elevated the expression of PGC-1? in myotubes and skeletal muscle and exerted promising therapeutic effects for treating type 2 diabetes.

SUBMITTER: Zhang LN 

PROVIDER: S-EPMC3609556 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Novel small-molecule PGC-1α transcriptional regulator with beneficial effects on diabetic db/db mice.

Zhang Li-Na LN   Zhou Hua-Yong HY   Fu Yan-Yun YY   Li Yuan-Yuan YY   Wu Fang F   Gu Min M   Wu Ling-Yan LY   Xia Chun-Mei CM   Dong Tian-Cheng TC   Li Jing-Ya JY   Shen Jing-Kang JK   Li Jia J  

Diabetes 20121218 4


Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has been shown to influence energy metabolism. Hence, we explored a strategy to target PGC-1α expression to treat metabolic syndromes. We developed a high-throughput screening assay that uses the human PGC-1α promoter to drive expression of luciferase. The effects of lead compound stimulation on PGC-1α expression in muscle cells and hepatocytes were investigated in vitro and in vivo. A novel small molecule, ZLN005, led to chang  ...[more]

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