Novel Small-Molecule PGC-1α Transcriptional Regulator With Beneficial Effects on Diabetic db/db Mice

  1. Jia Li
  1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
  1. Corresponding authors: Jia Li, jli{at}mail.shcnc.ac.cn, Jing-Ya Li, jyli{at}mail.shcnc.ac.cn, or Jing-Kang Shen, jkshen{at}mail.shcnc.ac.cn.

Abstract

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 changes in PGC-1α mRNA levels, glucose uptake, and fatty acid oxidation in L6 myotubes. Activation of AMP-activated protein kinase was involved in the induction of PGC-1α expression. In diabetic db/db mice, chronic administration of ZLN005 increased PGC-1α and downstream gene transcription in skeletal muscle, whereas hepatic PGC-1α 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-1α in myotubes and skeletal muscle and exerted promising therapeutic effects for treating type 2 diabetes.

Footnotes

  • Received June 2, 2012.
  • Accepted October 17, 2012.

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  1. Diabetes vol. 62 no. 4 1297-1307
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