T3 Induces Both Markers of Maturation and Aging in Pancreatic β-Cells

Abstract

Previously, we showed that thyroid hormone (TH) triiodothyronine (T₃) enhanced β-cell functional maturation through induction of <i>Mafa</i> High levels of T₃ 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 T₃ increased <i>p16^Ink4a</i> (a β-cell senescence marker and effector) mRNA in rodent and human β-cells. The kinetics of <i>Mafa</i> and <i>p16^Ink4a</i> 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 <i>p16^Ink4a</i> expression was controlled by THRA and <i>Mafa</i> 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 <i>p16^Ink4a</i> , whereas THRB1 bound to <i>Mafa</i> but not to <i>p16^Ink4a</i> On a cellular level, T₃ treatment accelerated cell senescence as shown by increased number of β-cells with acidic β-galactosidase activity. Our data show that T₃ can simultaneously induce both maturation (<i>Mafa</i>) and aging (<i>p16^Ink4a</i> ) 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 β-cells for replacement therapies in diabetes.