Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a key regulator of energy homeostasis. Dysregulation of PGC-1α is correlated with the development of insulin resistance and type 2 diabetes. ZLN005 is a small molecule that has been shown to increase the mRNA level of PGC-1α in L6 myotubes in a dose-dependent manner (5 – 20μM). It leds to a threefold increase in the PGC-1α gene expression over the control group at a concentration of 20μM after 24 h. ZLN005 at 10μM increased the mRNA expressions of GLUT4, NRF1, ERRα, cox5b, and acyl-CoA oxidase. ZLN005 at 20μM resulted in a 1.8-fold improvement in glucose uptake after 24 h of treatment. Chronic oral administration of db/db mice with 15mg/kg/day ZLN005 for 6 weeks improved glucose tolerance and pyruvate tolerance, and decreased insulin resistance in comparison with the control group. ZLN005 treatment also decreased the plasma non-esterified fatty acids and triglyceride levels in db/db mice by 20% and 37%, respectively[3].
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