Brain glucose utilization is markedly depressed in adult rats made cretinous after birth. To ascertain which subtype of thyroid hormone (TH) receptors, TRα1 or TRβ, is involved in the regulation of glucose utilization during brain development, we used the 2-[14C]deoxyglucose method in mice with a mutation in either their TRα or TRβ gene. A C insertion produced a frameshift mutation in their carboxyl terminus. These mutants lacked TH binding and transactivation activities and exhibited potent dominant negative activity. Glucose utilization in the homozygous TRβPV mutant mice and their wild-type siblings was almost identical in 19 brain regions, whereas it was markedly reduced in all brain regions of the heterozygous TRα1PV mice. These suggest that the α1 receptor mediates the TH effects in brain. Inasmuch as local cerebral glucose utilization is closely related to local synaptic activity, we also examined which thyroid hormone receptor is involved in the expression of synaptotagmin-related gene 1 (Srg1), a TH-positively regulated gene involved in the formation and function of synapses [Thompson, C. C. (1996) J. Neurosci. 16, 7832–7840]. Northern analysis showed that Srg1 expression was markedly reduced in the cerebellum of TRαPV/+ mice but not TRβPV/PV mice. These results show that the same receptor, TRα1, is involved in the regulation by TH of both glucose utilization and Srg1 expression.