Fig. 5: Schematic cartoon visualizing the effects of the inhibition of TNKS-mediated PARylation on PGC-1α and the metabolic consequences.
From: Tankyrase inhibition ameliorates lipid disorder via suppression of PGC-1α PARylation in db/db mice
PGC-1α is PARylated by TNKSs in adipose tissue and muscle and targeted for degradation. G007-LK inhibits the PARylation activity of TNKSs and, thereby, reduces the PARylation of PGC-1α, stabilizing its expression. This turns on specific PGC-1α-mediated transcriptional activity, leading to beneficial tissue-specific downstream effects: increase of mitochondrial mass and fatty acid (FA) oxidation in muscle, reduction of lipolysis-associated proteins ATGL and active HSL, increase of beiging-associated UCP-1 protein in adipose tissue, and upregulation of adiponectin in adipose tissue and serum. G007-LK treatment also ameliorates liver steatosis and downregulates serum cholesterol. These mechanisms contribute to the subsequent reduction of body weight gain and adiposity.
