T ₃ induces both markers of maturation and aging in pancreatic b-cells

Previously, we showed that thyroid hormone (TH) triiodothyronine (T ₃ ) enhanced b-cell functional maturation through induction of Mafa. High levels of T ₃ have been linked to decreased life span in mammals and low levels to lengthened life span, suggesting a relationship between TH and aging. Here, we show that T ₃ increased p16 ^Ink4a (a b-cell senescence marker and effector) mRNA in rodent and human b-cells. The kinetics of Mafa and p16 ^Ink4a induction suggested both genes as targets of TH via TH receptors (THRs) binding to specific response elements. Using specific agonists CO23 and GC1, we showed that p16 ^Ink4a expression was controlled by THRA and Mafa by THRB. Using chromatin immunoprecipitation and a transient transfection yielding biotinylated THRB1 or THRA isoforms to achieve specificity, we determined that THRA isoform bound to p16 ^Ink4a , whereas THRB1 bound to Mafa but not to p16 ^Ink4a . On a cellular level, T ₃ treatment accelerated cell senescence as shown by increased number of b-cells with acidic b-galactosidase activity. Our data show that T ₃ can simultaneously induce both maturation (Mafa) and aging (p16 ^Ink4a ) effectors and that these dichotomous effects are mediated through different THR isoforms. These findings may be important for further improving stem cell differentiation protocols to produce functional b-cells for replacement therapies in diabetes.