title: Hypothyroidism Induces Hypophagia Associated with Alterations in Protein Expression of Neuropeptide Y and Proopiomelanocortin in the Arcuate Nucleus, Independently of Hypothalamic Nuclei-Specific Changes in Leptin Signaling.
abstract: BACKGROUND
  Thyroid hormone and leptin are essential regulators of energy homeostasis. Both hormones stimulate energy expenditure but have opposite effects on appetite. The mechanisms behind food intake regulation in thyroid dysfunctions are poorly understood. It has been shown that hypothyroid rats exhibited impaired leptin anorexigenic effect and signaling in total hypothalamus, even though they were hypophagic. It was hypothesized that hypothyroidism modulates the expression of neuropeptides: orexigenic neuropeptide Y (NPY) and anorexigenic proopiomelanocortin (POMC), independently of inducing nuclei-specific changes in hypothalamic leptin signaling.
  
  
  METHODS
  Adult male rats were rendered hypothyroid by administration of 0.03% methimazole in the drinking water for 21 days. Protein content of NPY, POMC, and leptin signaling (the signal transducer and activator of transcription 3 [STAT3] pathway) were evaluated by Western blot, and mRNA levels by real time reverse transcription polymerase chain reaction in arcuate (ARC), ventromedial (VMN), and paraventricular (PVN) hypothalamic nuclei isolated from euthyroid (eu) and hypothyroid (hypo) rats. Leptin anorexigenic effect was tested by recording food intake for two hours after intracerebroventricular (i.c.v.) administration of leptin. Statistical differences were considered significant at p ≤ 0.05.
  
  
  RESULTS
  Hypothyroidism was confirmed by decreased serum triiodothyronine, thyroxine, and increased thyrotropin, in addition to increased levels of pro-TRH mRNA in PVN and Dio2 mRNA in the ARC of hypo rats. Hypothyroidism decreased body weight and food intake associated with decreased protein content of NPY and increased content of POMC in the ARC. Conversely, hypothyroidism induced central resistance to the acute anorexigenic effect of leptin, since while euthyroid rats displayed reduced food intake after leptin i.c.v. injection, hypothyroid rats showed no response. Hypothyroid rats exhibited decreased leptin receptor (ObRb) protein content in ARC and VMN but not in PVN nucleus. ObRb protein changes were concomitant with decreased phosphorylated STAT3 in the ARC, and decreased total STAT3 in VMN and PVN. However, hypothyroidism did not affect mRNA levels of Lepr or Stat3 in the hypothalamic nuclei.
  
  
  CONCLUSIONS
  Experimental hypothyroidism induced a negative energy balance accompanied by decreased NPY and increased POMC protein content in the ARC, resulting in predominance of anorexigenic pathways, despite central leptin resistance and impairment of the leptin signaling cascade in a nuclei-specific manner.
authors.affiliation: 1 Laboratory of Molecular Endocrinology, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil .
authors.forename: Camila
authors.initials: C
authors.lastname: Calvino
authors.affiliation: 2 Laboratory of Translational Endocrinology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil .
authors.forename: Güínever Eustáquio
authors.initials: GE
authors.lastname: Império
authors.affiliation: 1 Laboratory of Molecular Endocrinology, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil .
authors.forename: Marianna
authors.initials: M
authors.lastname: Wilieman
authors.affiliation: 1 Laboratory of Molecular Endocrinology, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil .
authors.forename: Ricardo Henrique
authors.initials: RH
authors.lastname: Costa-E-Sousa
authors.affiliation: 1 Laboratory of Molecular Endocrinology, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil .
authors.forename: Luana Lopes
authors.initials: LL
authors.lastname: Souza
authors.affiliation: 1 Laboratory of Molecular Endocrinology, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil .
authors.forename: Isis Hara
authors.initials: IH
authors.lastname: Trevenzoli
authors.affiliation: 1 Laboratory of Molecular Endocrinology, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil .
authors.forename: Carmen Cabanelas
authors.initials: CC
authors.lastname: Pazos-Moura
mesh_terms: D000818:Animals; D001069:Appetite Regulation; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004435:Eating; D004734:Energy Metabolism; D005247:Feeding Behavior; D007037:Hypothyroidism / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008713:Methimazole; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D017208:Rats, Wistar; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism / Q000503:physiopathology; D015431:Weight Loss; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D020738:Leptin; D008713:Methimazole; D009478:Neuropeptide Y; D011333:Pro-Opiomelanocortin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D013973:Thyrotropin-Releasing Hormone; D000097564:Iodothyronine Deiodinase Type II; C494088:Stat3 protein, rat