title: Inappropriate heat dissipation ignites brown fat thermogenesis in mice with a mutant thyroid hormone receptor α1.
abstract: Thyroid hormone is a major regulator of thermogenesis, acting both in peripheral organs and on central autonomic pathways. Mice heterozygous for a point mutation in thyroid hormone receptor α1 display increased thermogenesis as a consequence of high sympathetic brown fat stimulation. Surprisingly, despite the hypermetabolism, their body temperature is not elevated. Here we show, using isolated tail arteries, that defective thyroid hormone receptor α1 signaling impairs acetylcholine-mediated vascular relaxation as well as phenylephrine-induced vasoconstriction. Using infrared thermography on conscious animals, we demonstrate that these defects severely interfere with appropriate peripheral heat conservation and dissipation, which in turn leads to compensatory alterations in brown fat activity. Consequently, when the vasoconstrictive defect in mice heterozygous for a point mutation in thyroid hormone receptor α1 was reversed with the selective α1-adrenergic agonist midodrine, the inappropriate heat loss over their tail surface was reduced, normalizing brown fat activity and energy expenditure. Our analyses demonstrate that thyroid hormone plays a key role in vascular heat conservation and dissipation processes, adding a unique aspect to its well-documented functions in thermoregulation. The data thus facilitate understanding of temperature hypersensitivity in patients with thyroid disorders. Moreover, the previously unrecognized connection between cardiovascular regulation and metabolic activity revealed in this study challenges the interpretation of several experimental paradigms and questions some of the currently derived hypotheses on the role of thyroid hormone in thermogenesis.
authors.affiliation: Departments of Cell and Molecular Biology and Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Amy
authors.initials: A
authors.lastname: Warner
authors.forename: Awahan
authors.initials: A
authors.lastname: Rahman
authors.forename: Peter
authors.initials: P
authors.lastname: Solsjö
authors.forename: Kristina
authors.initials: K
authors.lastname: Gottschling
authors.forename: Benjamin
authors.initials: B
authors.lastname: Davis
authors.forename: Björn
authors.initials: B
authors.lastname: Vennström
authors.forename: Anders
authors.initials: A
authors.lastname: Arner
authors.forename: Jens
authors.initials: J
authors.lastname: Mittag
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature; D001833:Body Temperature Regulation / Q000502:physiology*; D007037:Hypothyroidism / Q000503:physiopathology*; D051379:Mice; D017354:Point Mutation / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013623:Tail / Q000098:blood supply; D022722:Thermogenesis / Q000502:physiology*; D013817:Thermography; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones
keywords: adipose tissue; tail temperature
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