Despite the relatively mild brain phenotype of D2KO or MCT8KO mice, their combined inactivation led to aggravated manifestation of thyroid hormone deprivation and resulted in similar effects as observed in hypothyroidism [9, 59].These data confirmed the crucial role of D2 in local T3 generation in the brain and suggested that changes in D2 expression could compensate for defects in MCT8 function in the rodent brain. This evidence concerns the gene DIO2 and hypothyroidism.