title: Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor alpha1.
abstract: Thyroid hormone, via its nuclear receptors TRalpha and TRbeta, controls metabolism by acting locally in peripheral tissues and centrally by regulating sympathetic signaling. We have defined aporeceptor regulation of metabolism by using mice heterozygous for a mutant TRalpha1 with low affinity to T3. The animals were hypermetabolic, showing strongly reduced fat depots, hyperphagia and resistance to diet-induced obesity accompanied by induction of genes involved in glucose handling and fatty acid metabolism in liver and adipose tissues. Increased lipid mobilization and beta-oxidation occurred in adipose tissues, whereas blockade of sympathetic signaling to brown adipose tissue normalized the metabolic phenotype despite a continued perturbed hormone signaling in this cell type. The results define a novel and important role for the TRalpha1 aporeceptor in governing metabolic homeostasis. Furthermore, the data demonstrate that a nuclear hormone receptor affecting sympathetic signaling can override its autonomous effects in peripheral tissues.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Sjögren
authors.forename: Anneke
authors.initials: A
authors.lastname: Alkemade
authors.forename: Jens
authors.initials: J
authors.lastname: Mittag
authors.forename: Kristina
authors.initials: K
authors.lastname: Nordström
authors.forename: Abram
authors.initials: A
authors.lastname: Katz
authors.forename: Björn
authors.initials: B
authors.lastname: Rozell
authors.forename: Håkan
authors.initials: H
authors.lastname: Westerblad
authors.forename: Anders
authors.initials: A
authors.lastname: Arner
authors.forename: Björn
authors.initials: B
authors.lastname: Vennström
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008660:Metabolism; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism / Q000502:physiology*
chemical_list: D005227:Fatty Acids; D008055:Lipids; D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha; D005947:Glucose