title: A thyroid hormone challenge in hypothyroid rats identifies T3 regulated genes in the hypothalamus and in models with altered energy balance and glucose homeostasis.
abstract: BACKGROUND
  The thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify components in the hypothalamus that may be involved in the action of T3 on energy balance regulatory mechanisms.
  
  
  METHODS
  Sprague Dawley rats were made hypothyroid by giving 0.025% methimazole (MMI) in their drinking water for 22 days. On day 21, half the MMI-treated rats received a saline injection, whereas the others were injected with T3. Food intake and body weight measurements were taken daily. Body composition was determined by magnetic resonance imaging, gene expression was analyzed by in situ hybridization, and T3-induced gene expression was determined by microarray analysis of MMI-treated compared to MMI-T3-injected hypothalamic RNA.
  
  
  RESULTS
  Post mortem serum thyroid hormone levels showed that MMI treatment decreased circulating thyroid hormones and increased thyrotropin (TSH). MMI treatment decreased food intake and body weight. Body composition analysis revealed reduced lean and fat mass in thyroidectomized rats from day 14 of the experiment. MMI treatment caused a decrease in circulating triglyceride concentrations, an increase in nonesterified fatty acids, and decreased insulin levels. A glucose tolerance test showed impaired glucose clearance in the thyroidectomized animals. In the brain, in situ hybridization revealed marked changes in gene expression, including genes such as Mct8, a thyroid hormone transporter, and Agrp, a key component in energy balance regulation. Microarray analysis revealed 110 genes to be up- or downregulated with T3 treatment (± 1.3-fold change, p<0.05). Three genes chosen from the differentially expressed genes were verified by in situ hybridization to be activated by T3 in cells located at or close to the hypothalamic ventricular ependymal layer and differentially expressed in animal models of long- and short-term body weight regulation.
  
  
  CONCLUSIONS
  This study identified genes regulated by T3 in the hypothalamus, a key area of the brain involved in homeostasis and neuroendocrine functions. These include genes hitherto not known to be regulated by thyroid status.
authors.affiliation: 1 Ingestive Behaviour Group, Rowett Institute for Nutrition and Health, University of Aberdeen , Aberdeen, United Kingdom .
authors.forename: Annika
authors.initials: A
authors.lastname: Herwig
authors.forename: Gill
authors.initials: G
authors.lastname: Campbell
authors.forename: Claus-Dieter
authors.initials: CD
authors.lastname: Mayer
authors.forename: Anita
authors.initials: A
authors.lastname: Boelen
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Ross
authors.forename: Julian G
authors.initials: JG
authors.lastname: Mercer
authors.forename: Perry
authors.initials: P
authors.lastname: Barrett
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001823:Body Composition / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D007037:Hypothyroidism / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008713:Methimazole; D051381:Rats; D017207:Rats, Sprague-Dawley; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D014284:Triiodothyronine; D008713:Methimazole
references.citation: Mol Endocrinol. 2002 Nov;16(11):2547-60
references.pmid: 12403844
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5966-71
references.pmid: 19321430
references.citation: J Clin Invest. 2000 Apr;105(7):1005-11
references.pmid: 10749579
references.citation: J Biol Chem. 2003 Oct 10;278(41):40128-35
references.pmid: 12871948
references.citation: FEBS Lett. 2005 Aug 29;579(21):4654-8
references.pmid: 16098513
references.citation: J Neuroendocrinol. 2008 May;20(5):576-86
references.pmid: 18363803
references.citation: Am J Physiol Regul Integr Comp Physiol. 2009 Apr;296(4):R1180-9
references.pmid: 19158410
references.citation: Clin Endocrinol (Oxf). 2001 Aug;55(2):233-9
references.pmid: 11531931
references.citation: Endocrinology. 2009 Feb;150(2):1025-32
references.pmid: 18845642
references.citation: Endocrinology. 2009 Jun;150(6):2611-7
references.pmid: 19213832
references.citation: Am J Physiol Regul Integr Comp Physiol. 2009 May;296(5):R1307-15
references.pmid: 19297543
references.citation: Front Neuroendocrinol. 2007 Aug-Sep;28(2-3):97-114
references.pmid: 17588648
references.citation: Endocrinology. 2005 Jun;146(6):2827-33
references.pmid: 15746256
references.citation: J Physiol. 2011 May 1;589(Pt 9):2275-86
references.pmid: 21486800
references.citation: Thyroid Res. 2011 Aug 03;4 Suppl 1:S7
references.pmid: 21835054
references.citation: Biochim Biophys Acta. 1962 Jul 16;60:461-79
references.pmid: 13919773
references.citation: Mol Endocrinol. 2002 Oct;16(10):2283-96
references.pmid: 12351693
references.citation: Nucleic Acids Res. 2002 Jan 1;30(1):207-10
references.pmid: 11752295
references.citation: EMBO J. 2007 Oct 31;26(21):4535-45
references.pmid: 17932484
references.citation: J Biol Chem. 2005 May 20;280(20):20010-20
references.pmid: 15753094
references.citation: Am J Physiol Regul Integr Comp Physiol. 2000 Jan;278(1):R271-81
references.pmid: 10644649
references.citation: Endocrinology. 2008 Oct;149(10):4829-36
references.pmid: 18566119
references.citation: J Clin Endocrinol Metab. 2007 Feb;92(2):491-6
references.pmid: 17090642
references.citation: J Biol Chem. 2003 Oct 31;278(44):43489-95
references.pmid: 12923172
references.citation: Endocrinology. 1985 Dec;117(6):2435-42
references.pmid: 3840737
references.citation: Endocrinology. 1977 Apr;100(4):980-8
references.pmid: 556986
references.citation: Nature. 1997 Jan 9;385(6612):165-8
references.pmid: 8990120
references.citation: Peptides. 2001 Jan;22(1):129-34
references.pmid: 11179607
references.citation: J Neuroendocrinol. 2008 Jun;20(6):827-33
references.pmid: 18601706
references.citation: Proc Natl Acad Sci U S A. 1989 Sep;86(18):7250-4
references.pmid: 2780568
references.citation: Diabetes. 2004 May;53(5):1230-6
references.pmid: 15111491
references.citation: PLoS One. 2010 Feb 09;5(2):e9098
references.pmid: 20161732
references.citation: Cell Metab. 2007 Jan;5(1):21-33
references.pmid: 17189204
references.citation: J Biol Chem. 2004 Aug 27;279(35):36650-9
references.pmid: 15194686
references.citation: Brain Res. 1991 Jul 19;554(1-2):229-36
references.pmid: 1933305
references.citation: J Neurosci. 2013 Apr 3;33(14):6170-80
references.pmid: 23554498
references.citation: Cell Cycle. 2006 Sep;5(17):1913-7
references.pmid: 16929182
references.citation: Endocrinology. 2000 Nov;141(11):4309-12
references.pmid: 11089566
references.citation: Methods Enzymol. 1982;84:272-303
references.pmid: 7048011
references.citation: Endocr Rev. 2002 Feb;23(1):38-89
references.pmid: 11844744
references.citation: Eur J Pharmacol. 2002 Apr 12;440(2-3):85-98
references.pmid: 12007527
references.citation: Endocrinology. 1998 Oct;139(10):4428-31
references.pmid: 9751529
references.citation: J Neuroendocrinol. 2010 Mar;22(3):153-65
references.pmid: 20041985
references.citation: Nature. 1963 Mar 23;197:1167-8
references.pmid: 13993433
references.citation: J Neuroendocrinol. 2009 Jul;21(7):610-9
references.pmid: 19490367
references.citation: Endocrinology. 2004 Apr;145(4):1649-55
references.pmid: 14684601
references.citation: J Mol Endocrinol. 2012 Jun 26;49(1):R29-35
references.pmid: 22586142
references.citation: Am J Physiol. 1995 Nov;269(5 Pt 2):R1099-106
references.pmid: 7503297
references.citation: Nat Neurosci. 2005 Oct;8(10):1289-91
references.pmid: 16158063
references.citation: Science. 1997 Oct 3;278(5335):135-8
references.pmid: 9311920
references.citation: Am J Physiol Regul Integr Comp Physiol. 2000 Jul;279(1):R47-52
references.pmid: 10896863
references.citation: Endocrinology. 2007 Aug;148(8):3608-17
references.pmid: 17478556
references.citation: Nat Med. 2010 Sep;16(9):1001-8
references.pmid: 20802499
references.citation: J Clin Invest. 1990 Sep;86(3):889-99
references.pmid: 2394838
references.citation: Endocrinology. 1975 Jul;97(1):91-101
references.pmid: 49266
references.citation: J Endocrinol. 2006 Dec;191(3):707-14
references.pmid: 17170227
references.citation: Obes Facts. 2008;1(2):71-9
references.pmid: 20054165
references.citation: Physiol Rev. 2006 Apr;86(2):435-64
references.pmid: 16601266
references.citation: Thyroid. 1999 Dec;9(12):1265-71
references.pmid: 10646670
references.citation: S Afr Med J. 2003 Jul;93(7):529-31
references.pmid: 12939927
references.citation: Endocrinology. 2012 Sep;153(9):4128-35
references.pmid: 22759379
references.citation: Diabetes Metab Res Rev. 2001 May-Jun;17(3):164-74
references.pmid: 11424229
references.citation: J Clin Endocrinol Metab. 2005 Feb;90(2):904-12
references.pmid: 15562027
references.citation: Prog Brain Res. 2006;153:209-35
references.pmid: 16876577
references.citation: Nat Neurosci. 2012 Mar 25;15(5):700-2
references.pmid: 22446882
references.citation: Endocrinology. 1998 Jun;139(6):2879-84
references.pmid: 9607797
references.citation: FASEB J. 2014 Apr;28(4):1534-42
references.pmid: 24334705
references.citation: Biosci Rep. 2005 Jun-Aug;25(3-4):191-208
references.pmid: 16283553
references.citation: J Clin Invest. 2013 Apr;123(4):1492-500
references.pmid: 23524969