Brain glucose utilization in mice with a targeted mutation in the thyroid hormone alpha or beta receptor gene.
Brain glucose utilization is markedly depressed in adult rats made cretinous after birth. To ascertain which subtype of thyroid hormone (TH) receptors, TRalpha1 or TRbeta, is involved in the regulation of glucose utilization during brain development, we used the 2-[(14)C]deoxyglucose method in mice with a mutation in either their TRalpha or TRbeta 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 TRbetaPV 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 TRalpha1PV mice. These suggest that the alpha1 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 TRalpha(PV/+) mice but not TRbeta(PV/PV) mice. These results show that the same receptor, TRalpha1, is involved in the regulation by TH of both glucose utilization and Srg1 expression.
Itoh
Y
Y
Laboratory of Cerebral Metabolism, National Institute of Mental Health, and National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4030, USA.
Esaki
T
T
Kaneshige
M
M
Suzuki
H
H
Cook
M
M
Sokoloff
L
L
Cheng
S Y
SY
Nunez
J
J
D000367:Age Factors; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004734:Energy Metabolism / Q000235:genetics*; D016368:Frameshift Mutation; D005786:Gene Expression Regulation / Q000235:genetics; D018390:Gene Targeting; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013963:Thyroid Hormones / Q000502:physiology; D015533:Transcriptional Activation / Q000235:genetics; D033921:Vesicular Transport Proteins
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011988:Receptors, Thyroid Hormone; C424133:Sytl1 protein, mouse; D013963:Thyroid Hormones; D033921:Vesicular Transport Proteins; D003847:Deoxyglucose; D005947:Glucose