title: The complementary and divergent roles of uncoupling proteins 1 and 3 in thermoregulation.
abstract: Both uncoupling protein 1 (UCP1) and UCP3 are important for mammalian thermoregulation. UCP1 and UCP3 in brown adipose tissue mediate early and late phases of sympathomimetic thermogenesis, respectively. Lipopolysaccharide thermogenesis requires skeletal muscle UCP3 but not UCP1. Acute noradrenaline-induced hyperthermia requires UCP1 but not UCP3. Loss of both UCP1 and UCP3 accelerate the loss of body temperature compared to UCP1KO alone during acute cold exposure.
  
  
  
  Uncoupling protein 1 (UCP1) is the established mediator of brown adipose tissue-dependent thermogenesis. In contrast, the role of UCP3, expressed in both skeletal muscle and brown adipose tissue, in thermoregulatory physiology is less well understood. Here, we show that mice lacking UCP3 (UCP3KO) have impaired sympathomimetic (methamphetamine) and completely abrogated lipopolysaccharide (LPS) thermogenesis, but a normal response to noradrenaline. By comparison, UCP1 knockout (UCP1KO) mice exhibit blunted methamphetamine and fully inhibited noradrenaline thermogenesis, but an increased febrile response to LPS. We further establish that mice lacking both UCP1 and 3 (UCPDK) fail to show methamphetamine-induced hyperthermia, and have a markedly accelerated loss of body temperature and survival after cold exposure compared to UCP1KO mice. Finally, we show that skeletal muscle-specific human UCP3 expression is able to significantly rescue LPS, but not sympathomimetic thermogenesis blunted in UCP3KO mice. These studies identify UCP3 as an important mediator of physiological thermogenesis and support a renewed focus on targeting UCP3 in metabolic physiology.
authors.affiliation: Department of Molecular Biosciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX, 78712, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Riley
authors.affiliation: Division of Pharmacy and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Dao
authors.affiliation: Division of Pharmacy and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.
authors.forename: M Alexander
authors.initials: MA
authors.lastname: Kenaston
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Cosenza, Italy.
authors.forename: Luigina
authors.initials: L
authors.lastname: Muto
authors.affiliation: Division of Pharmacy and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.
authors.forename: Shohei
authors.initials: S
authors.lastname: Kohno
authors.affiliation: Department of Biochemistry, The University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Nowinski
authors.affiliation: Department of Molecular Biosciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX, 78712, USA.|Division of Pharmacy and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Solmonson
authors.affiliation: Division of Pharmacy and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pfeiffer
authors.affiliation: National Heart, Lung, and Blood Institute, Laboratory of Mitochondrial Biology and Metabolism, NIH, Bethesda, MD, 20892, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Sack
authors.affiliation: Cardiovascular and Pulmonary Branch and the Department of Biochemistry and Molecular Medicine, George Washington University, and the Veterans Affairs Medical Center, Washington, DC, 20422, 20052, USA.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Biosciences, Biotechnologies, and Biopharmaceutics and Center of Excellence in Comparative Genomics, University of Bari, 70125, Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fiermonte
authors.affiliation: The Ohio Attorney General's Center for the Future of Forensic Science, Bowling Green State University, Bowling Green, OH, 43403, USA.
authors.forename: Jon E
authors.initials: JE
authors.lastname: Sprague
authors.affiliation: Division of Pharmacy and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Mills
mesh_terms: D000818:Animals; D001833:Body Temperature Regulation / Q000502:physiology*; D003080:Cold Temperature; D006979:Hyperthermia, Induced; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009638:Norepinephrine / Q000494:pharmacology; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000502:physiology*; D000071247:Uncoupling Protein 3 / Q000235:genetics / Q000502:physiology*
chemical_list: D008070:Lipopolysaccharides; C000604392:UCP3 protein, human; C000604372:Ucp1 protein, mouse; C000604393:Ucp3 protein, mouse; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; D008694:Methamphetamine; D009638:Norepinephrine
keywords: LPS; brown adipose tissue; methamphetamine; skeletal muscle; sympathomimetic; thermogenesis; uncoupling protein