title: A thyroid hormone receptor alpha gene mutation (P398H) is associated with visceral adiposity and impaired catecholamine-stimulated lipolysis in mice.
abstract: Thyroid hormone has profound effects on metabolic homeostasis, regulating both lipogenesis and lipolysis, primarily by modulating adrenergic activity. We generated mice with a point mutation in the thyroid hormone receptor alpha (TRalpha) gene producing a dominant-negative TRalpha mutant receptor with a proline to histidine substitution (P398H). The heterozygous P398H mutant mice had a 3.4-fold (p < 0.02) increase in serum thyrotropin (TSH) levels. Serum triiodothyronine (T3) and thyroxine (T4) concentrations were slightly elevated compared with wild-type mice. The P398H mice had a 4.4-fold increase in body fat (as a fraction of total body weight) (p < 0.001) and a 5-fold increase in serum leptin levels (p < 0.005) compared with wild-type mice. A 3-fold increase in serum fasting insulin levels (p < 0.002) and a 55% increase in fasting glucose levels (p < 0.01) were observed in P398H compared with wild-type mice. There was a marked reduction in norepinephrine-induced lipolysis, as reflected in reduced glycerol release from white adipose tissue isolated from P398H mice. Heart rate and cold-induced adaptive thermogenesis, mediated by thyroid hormone-catecholamine interaction, were also reduced in P398H mice. In conclusion, the TRalpha P398H mutation is associated with visceral adiposity and insulin resistance primarily due to a marked reduction in catecholamine-stimulated lipolysis. The observed phenotype in the TRalpha P398H mouse is likely due to interference with TRalpha action as well as influence on other metabolic signaling pathways. The physiologic significance of these findings will ultimately depend on understanding the full range of actions of this mutation.
authors.affiliation: Molecular Endocrinology Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Departments of Medicine and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90073, USA.
authors.forename: Yan-Yun
authors.initials: YY
authors.lastname: Liu
authors.forename: James J
authors.initials: JJ
authors.lastname: Schultz
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Brent
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D002352:Carrier Proteins / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D005799:Genes, Dominant; D005947:Glucose / Q000096:biosynthesis; D005993:Glycerolphosphate Dehydrogenase / Q000378:metabolism; D006579:Heterozygote; D006639:Histidine / Q000737:chemistry; D007328:Insulin / Q000097:blood; D007473:Ion Channels; D020738:Leptin / Q000097:blood; D008066:Lipolysis; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins; D009154:Mutation; D009638:Norepinephrine / Q000378:metabolism; D010641:Phenotype; D017354:Point Mutation; D011392:Proline / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D011941:Receptors, Adrenergic / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013696:Temperature; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics*; D013963:Thyroid Hormones / Q000378:metabolism; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D013997:Time Factors; D014284:Triiodothyronine / Q000097:blood; D000071256:Uncoupling Protein 1
chemical_list: D002352:Carrier Proteins; D002395:Catecholamines; D007328:Insulin; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D011941:Receptors, Adrenergic; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D000071256:Uncoupling Protein 1; D014284:Triiodothyronine; D006639:Histidine; D013972:Thyrotropin; D011392:Proline; D005993:Glycerolphosphate Dehydrogenase; D005947:Glucose; D013974:Thyroxine; D009638:Norepinephrine