| First Author | Zhang LN | Year | 2013 |
| Journal | Diabetes | Volume | 62 |
| Issue | 4 | Pages | 1297-307 |
| PubMed ID | 23250358 | Mgi Jnum | J:208587 |
| Mgi Id | MGI:5563737 | Doi | 10.2337/db12-0703 |
| Citation | Zhang LN, et al. (2013) Novel small-molecule PGC-1alpha transcriptional regulator with beneficial effects on diabetic db/db mice. Diabetes 62(4):1297-307 |
| abstractText | Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) has been shown to influence energy metabolism. Hence, we explored a strategy to target PGC-1alpha expression to treat metabolic syndromes. We developed a high-throughput screening assay that uses the human PGC-1alpha promoter to drive expression of luciferase. The effects of lead compound stimulation on PGC-1alpha expression in muscle cells and hepatocytes were investigated in vitro and in vivo. A novel small molecule, ZLN005, led to changes in PGC-1alpha mRNA levels, glucose uptake, and fatty acid oxidation in L6 myotubes. Activation of AMP-activated protein kinase was involved in the induction of PGC-1alpha expression. In diabetic db/db mice, chronic administration of ZLN005 increased PGC-1alpha and downstream gene transcription in skeletal muscle, whereas hepatic PGC-1alpha 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-1alpha in myotubes and skeletal muscle and exerted promising therapeutic effects for treating type 2 diabetes. |
