Tankyrase-2 regulates adipocyte differentiation through AMPK/mTOR signaling.

Although tankyrases (TNKSs) were originally described as enzymes safeguarding genome integrity, TNKSs are also associated with metabolism and are involved in the differentiation of multiple cell lineages including adipocytes. Here we aimed to understand the role of TNKSs specifically in adipocyte differentiation. We found that the deletion of TNKS1 or TNKS2 decreased the rate of adipocyte differentiation. Furthermore, the loss of TNKs induced a multi-pronged cellular adaptation characterized by changes in cellular proteostasis centered around the inhibition of autophagy, AMPK activation and the suppression of mTORC1 activity. Deleting TNKSs also induced mitochondrial oxidative phosphorylation and glycolytic flux. Interestingly, the fraction of oligomycin-resistant respiration decreased, suggesting more coupled OXPHOS. However, the lower differentiation rate of TNKS2 knockout cells was salvaged by pharmacological activation of autophagy (by NV-5138) and the pharmacological inhibition of LKB1 (by HY-10371), an upstream suppressor of the mTOR system. Finally, TNKS2 can ADP-ribosylate LKB1, rendering it susceptible for ubiquitinylation that appears to be a key step towards committing adipocytes to differentiation. Together this data validates the use of TNK inhibitors for managing metabolic diseases and raises the possibility that TNK inhibition can influence tumor or immunometabolism and amplify the effects of other treatments.