title: Essential role of UCP1 modulating the central effects of thyroid hormones on energy balance.
abstract: OBJECTIVE
  Classically, metabolic effects of thyroid hormones (THs) have been considered to be peripherally mediated, i.e. different tissues in the body respond directly to thyroid hormones with an increased metabolism. An alternative view is that the metabolic effects are centrally regulated. We have examined here the degree to which prolonged, centrally infused triiodothyronine (T3) could in itself induce total body metabolic effects and the degree to which brown adipose tissue (BAT) thermogenesis was essential for such effects, by examining uncoupling protein 1 (UCP1) KO mice.
  
  
  METHODS
  Wildtype and UPC1 KO mice were centrally-treated with T3 by using minipumps. Metabolic measurements were analyzed by indirect calorimetry and expression analysis by RT-PCR or western blot. BAT morphology and histology were studied by immunohistochemistry.
  
  
  RESULTS
  We found that central T3-treatment led to reduced levels of hypothalamic AMP-activated protein kinase (AMPK) and elevated body temperature (0.7 °C). UCP1 was essential for the T3-induced increased rate of energy expenditure, which was only observable at thermoneutrality and notably only during the active phase, for the increased body weight loss, for the increased hypothalamic levels of neuropeptide Y (NPY) and agouti-related peptide (AgRP) and for the increased food intake induced by central T3-treatment. Prolonged central T3-treatment also led to recruitment of BAT and britening/beiging ("browning") of inguinal white adipose tissue (iWAT).
  
  
  CONCLUSIONS
  We conclude that UCP1 is essential for mediation of the central effects of thyroid hormones on energy balance, and we suggest that similar UCP1-dependent effects may underlie central energy balance effects of other agents.
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain.
authors.forename: Mayte
authors.initials: M
authors.lastname: Alvarez-Crespo
authors.affiliation: The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91, Stockholm, Sweden.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Csikasz
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Martínez-Sánchez
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.affiliation: The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91, Stockholm, Sweden.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cannon
authors.affiliation: The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91, Stockholm, Sweden. Electronic address: jan@metabol.su.se.
authors.forename: Jan
authors.initials: J
authors.lastname: Nedergaard
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain. Electronic address: m.lopez@usc.es.
authors.forename: Miguel
authors.initials: M
authors.lastname: López
keywords: AMPK; Brown adipose tissue; Hypothalamus; Thyroid hormones; UCP1