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DOI: 10.1055/s-0031-1277187
© Georg Thieme Verlag KG Stuttgart · New York
Supraphysiological Triiodothyronine Doses Diminish Leptin and Adiponectin Gene Expression, but do not Alter Resistin Expression in Calorie Restricted Obese Rats
Publication History
received 08.12.2010
accepted 12.04.2011
Publication Date:
09 May 2011 (online)

Abstract
Thyroid hormones regulate energy balance and act on adipokines. However, while it is unclear what the effects are of calorie restriction and high doses of triiodothyronine (T3) on adipokines in obesity, thyroid hormones are illicitly administered in isolation or in association with a hypocaloric diet as an obesity treatment. The present study determined the effect of T3 on serum concentrations and gene expression of the adipokines leptin, resistin, and adiponectin in calorie-restricted obese rats. Male Wistar rats received a hypercaloric diet for 20 weeks followed by calorie restriction for 8 weeks. The animals were then randomly divided into 3 groups: calorie restriction (OR), OR with 5 μg of T3/100 g BW (RS1), and OR with 25 μg of T3/100 g BW (RS2) for 2 weeks. Blood and adipose tissue samples were collected for biochemical, hormonal, and gene expression analyses. Serum concentrations of leptin (OR: 3.7±0.6, RS1: 3.8±1, RS2 0.2±0.07 ng/dl) and resistin (OR: 2.5±0.6, RS1: 2.5±0.5, RS2 1.6±0.3 ng/dl) were diminished at the higher dose, while serum adiponectin (OR: 31±7, RS1: 24±5, RS2 26±7 ng/dl) levels were lower in the low dose group. Administration of T3 reduced leptin gene expression (OR: 0.91±0.1, RS1: 0.95±0.1, RS2 0.22±0.1) only at the higher dose, resistin expression (OR: 1.06±0.2, RS1: 1.04±0.1, RS2 0.88±0.2) was not influenced by T3 treatment, and adiponectin expression (OR: 1.55±0.5, RS1: 0.95±0.15, RS2 0.97±0.13) was diminished independent of the T3 dose. These results indicate that T3, directly or indirectly, inhibits the expression of leptin and adiponectin in calorie restricted obese animals.
Key words
thyroid hormone - adipose tissue - high-fat diet - food deprivation
References
- 1
Flier JS, Harris M, Hollenberg AN.
Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring.
J Clin Invest.
2000;
105
859-861
Reference Ris Wihthout Link
- 2
Feldt-Rasmussen U.
Thyroid and leptin.
Thyroid.
2007;
17
413-419
Reference Ris Wihthout Link
- 3
Reinerh T, Andler W.
Thyroid hormones before and after weight loss in obesity.
Archives of Disease in Childhood.
2002;
87
320-326
Reference Ris Wihthout Link
- 4
Douyon L, Schteingart DE.
Effect of obesity and starvation on thyroid hormone, growth hormone, and cortisol
secretion.
Endocrinol Metab Clin North Am.
2002;
31
173-189
Reference Ris Wihthout Link
- 5
Ahima RS.
Leptin and neuroendocrinology of fasting.
Front Horm Res.
2000;
26
42-56
Reference Ris Wihthout Link
- 6
Krotkiewski M.
Thyroid hormones and treatment of obesity.
Int J Obes Relat Metab Disord.
2000;
24
S116-S119
Reference Ris Wihthout Link
- 7
Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR.
Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine
selenodeiodinases.
Endocr Rev.
2002;
23
38-89
Reference Ris Wihthout Link
- 8
Pinkney JH, Goodrick SJ, Katz J, Johnson AB, Lightman SL, Coppack SW, Mohamed-Ali V.
Leptin and the pituitary-thyroid axis: a comparative study in lean, obese, hypothyroid
and hyperthyroid subjects.
Clin Endocrinol.
1998;
49
583-588
Reference Ris Wihthout Link
- 9
Tilg H, Moschen AR.
Adipocytokines: mediators linking adipose tissue, inflammation, and immunity.
Nat Rev Immunol.
2006;
6
772-783
Reference Ris Wihthout Link
- 10
Ahima RS, Qi Y, Singhal NS, Jackson MB, Scherer PE.
Brain adipocytokine action and metabolic regulation.
Diabetes.
2006;
55
(S 02)
S145-S154
Reference Ris Wihthout Link
- 11
Viguerie N, Vidal H, Arner P, Holst C, Verdich C, Avizou S, Astrup A, Saris WH, Macdonald IA, Klimcakova E, Clément K, Martinez A, Hoffstedt J, Sørensen TI, Langin D.
Adipose tissue gene expression in obese subjects during low-fat and high-fat hypocaloric
diets.
Diabetologia.
2005;
48
123-131
Reference Ris Wihthout Link
- 12
Giacobino JP.
Uncoupling proteins, leptin and obesity: an update review.
Ann N Y Acad Sci.
2002;
967
398-402
Reference Ris Wihthout Link
- 13
Legradi G, Emerson CH, Ahima RS, Flier JS, Lechan RM.
Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger
ribonucleic acid in neurons of the hypothalamic paraventricular nucleus.
Endocrinol.
1997;
138
2569-2576
Reference Ris Wihthout Link
- 14
Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS.
Role of leptin in the neuroendocrine response to fasting.
Nature.
1996;
382
250-252
Reference Ris Wihthout Link
- 15
Menendez C, Baldelli R, Camina JP, Escudero B, Peino R, Dieguez C, Casanueva FF.
TSH stimulates leptin secretion by a direct effect on adipocytes.
J Endocrinol.
2003;
176
7-12
Reference Ris Wihthout Link
- 16
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA.
The hormone resistin links obesity to diabetes.
Nature.
2001;
409
307-312
Reference Ris Wihthout Link
- 17
Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, Nelson C, Lowman HB, Wright BD, Skelton NJ, Frantz GD, Tumas DB, Peale Jr FV, Shelton DL, Hébert CC.
FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation,
defines a new gene family.
EMBO J.
2000;
19
4046-4055
Reference Ris Wihthout Link
- 18
Meier U, Gressner AM.
Endocrine Regulation of Energy Metabolism: Review of pathobiochemical and clinical
chemical aspects of leptin, ghrelin, adiponectin, and resistin.
Clin Chem.
2004;
50
1511-1525
Reference Ris Wihthout Link
- 19
Nogueiras R, Gualillo O, Caminos JE, Casanueva FF, Diéguez C.
Regulation of resistin by gonadal, thyroid hormone, and nutritional status.
Obes Res.
2003;
11
408-414
Reference Ris Wihthout Link
- 20
Krassas GE, Pontikides N, Loustis K, Koliakos G, Constantinidis T, Panidis D.
Resistin levels in hyperthyroid patients before and after restoration of thyroid function:
relationship with body weight and body composition.
Eur J Endocrinol.
2005;
153
217-221
Reference Ris Wihthout Link
- 21
Iglesias P, Alvarez FP, Codoceo R, Díez JJ.
Serum concentrations of adipocytokines in patients with hyperthyroidism and hypothyroidism
before and after control of thyroid function.
Clin Endocrinol (Oxf).
2003;
59
621-629
Reference Ris Wihthout Link
- 22
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE.
The adipocyte-secreted protein Acrp30 enhances hepatic insulin action.
Nat Med.
2001;
7
947-953
Reference Ris Wihthout Link
- 23
Nascimento AF, Sugizaki MM, Leopoldo AS, Lima-Leopoldo AP, Nogueira CR, Novelli EL, Padovani CR, Cicogna AC.
Misclassification probability as obese or lean in hypercaloric and normocaloric diet.
Biol Res.
2008;
41
253-259
Reference Ris Wihthout Link
- 24
Silva FG, Giannocco G, Santos MF, Nunes MT.
Thyroid hormone induction of actin polymerization in somatotrophs of hypothyroid rats:
potential repercussions in growth hormone synthesis and secretion.
Endocrinol.
2006;
147
5777-5785
Reference Ris Wihthout Link
- 25
Giannocco G, Santos RA, Nunes MT.
Thyroid hormone stimulates myoglobin gene expression in rat cardiac muscle.
Mol Cell Endocrinol.
2004;
226
19-26
Reference Ris Wihthout Link
- 26
Fernández-Galaz C, Fernández-Agulló T, Pérez C, Peralta S, Arribas C, Andrés A, Carrascosa JM, Ros M.
Long-term food restriction prevents ageing-associated central leptin resistance in
wistar rats.
Diabetologia.
2002;
45
997-1003
Reference Ris Wihthout Link
- 27
Minatoya Y, Ito K, Kagaya Y, Asaumi Y, Takeda M, Nakayama M.
Depressed contractile reserve and impaired calcium handling of cardiac myocytes from
chronically unloaded hearts are ameliorated with the administration of physiological
treatment dose of T3 in rats.
Acta Physiol.
2007;
189
221-231
Reference Ris Wihthout Link
- 28
Kokkinos A, Mourouzis I, Kyriaki D, Pantos C, Katsilambros N, Cokkinos DV.
Possible implications of leptin, adiponectin and ghrelin in the regulation of energy
homeostasis by thyroid hormone.
Endocrine.
2007;
32
30-32
Reference Ris Wihthout Link
- 29
Levin BE, Dunn-Meynell AA.
Reduced central leptin sensitivity in rats with diet-induced obesity.
Am J Physiol Regul Integr Comp Physiol.
2002;
283
R941-R948
Reference Ris Wihthout Link
- 30
Boustany CM, Bharadwaj K, Daugherty A, Brown DR, Randall DC, Cassis LA.
Activation of the systemic and adipose renin-angiotensin system in rats with diet-induced
obesity and hypertension.
Am J Physiol Regul Integr Comp Physiol.
2004;
287
R943-R949
Reference Ris Wihthout Link
- 31
Livak KJ, Schmittgen TD.
Analysis of relative gene expression data using real-time quantitative PCR and the
2-[Delta][Delta]CT method.
Methods.
2001;
25
402-408
Reference Ris Wihthout Link
- 32
Alonso A, Fernández Y, Fernández R, Ordóñez P, Moreno M, Díaz F, Patterson AM, González C.
Effect of food restriction on the insulin signalling pathway in rat skeletal muscle
and adipose tissue.
J Nutr Biochem.
2005;
16
602-609
Reference Ris Wihthout Link
- 33
Spindler SR.
Rapid and reversible induction of the longevity, anticancer and genomic effects of
caloric restriction.
Mech Ageing Dev.
2005;
126
960-966
Reference Ris Wihthout Link
- 34
Moore R, Grant AM, Howard AN, Mills IH.
Treatment of obesity with triiodothyronine and a very-low-calorie liquid formula diet.
Lancet.
1980;
1
223-226
Reference Ris Wihthout Link
- 35
Moreira-Andrés MN, Del Cañizo-Gómez FJ, Black EG, Hoffenberg R.
Long-term evaluation of thyroidal response to partial calorie restriction in obesity.
Clin Endocrinol (Oxf).
1981;
15
621-626
Reference Ris Wihthout Link
- 36
Biondi B, Palmieri EA, Fazio S, Cosco C, Nocera M, Saccà L, Filetti S, Lombardi G, Perticone F.
Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology
and function in young and middle-aged patients.
J Clin Endocrinol Metab.
2000;
85
4701-4705
Reference Ris Wihthout Link
- 37
Brennam MD, Powell C, Kaufman KR, Sun PC, Bahn RS, Nair KS.
The impact of overt and subclinical hyperthyroidism on skeletal muscle.
Thyroid.
2006;
16
375-380
Reference Ris Wihthout Link
- 38
Magsino Junior C, Hamouda W, Ghanim H, Browne R, Aljada A, Dandona P.
Effect of triiodothyronine on reactive oxygen species generation by leukocytes, indices
of oxidative damage, and antioxidant reserve.
Metabolism.
2000;
49
799-803
Reference Ris Wihthout Link
- 39
Zabrocka L, Klimek J, Swierczynski J.
Evidence that triiodothyronine decreases rat serum leptin concentration by down-regulation
of leptin gene expression in white adipose tissue.
Life Sciences.
2006;
79
1114-1120
Reference Ris Wihthout Link
- 40 Larsen PR, Davies TF, Schlumberger MJ, Hay ID. Thyroid physiology and diagnostic evaluation of patients with thyroid disorders. In:, Kronenberg HM,, Melmed S,, Polonsky KS,, Larsen PR, (eds). Williams Textbook of Endocrinology. 11th ed. Philadelphia: Saunders Elsevier; 2008: 299-332
Reference Ris Wihthout Link
- 41
Krotkiewski M.
Thyroid hormones in the pathogenesis and treatment of obesity.
Eur J Pharmacol.
2002;
440
85-98
Reference Ris Wihthout Link
- 42
Dimitriadis GD, Raptis SA.
Thyroid hormone excess and glucose intolerance.
Exp Clin Endocrinol Diab.
2001;
109
S225-S239
Reference Ris Wihthout Link
- 43
Setia S, Sridhar MG, Koner BC, Bobby Z, Bhat V, Chaturvedula L.
Increased insulin sensitivity in intrauterine growth retarded newborns – Do thyroid
hormones play a role?.
Clinica Chimica Acta.
2006;
4p
Reference Ris Wihthout Link
- 44
Kung A, Pang R, Lander I, Lam k, Janus E.
Changes in serum lipoprotein (a) and lipids during treatment of hyperthyroidism.
Clin Chem.
1995;
41
226-231
Reference Ris Wihthout Link
- 45
Duntas LH.
Thyroid disease and lipids.
Thyroid.
2002;
12
287-293
Reference Ris Wihthout Link
- 46
Riis ALD, Gravholt CH, Djurhuus CB, Norrelund H, Jorgensen JOL, Weeke J, Moller N.
Elevated regional lipolysis in hyperthyroidism.
J Clin Endocrinol Metab.
2002;
87
4747-4753
Reference Ris Wihthout Link
- 47
Holmes JH, Lambourne LJ.
The relation between plasma free fatty acid concentration and the digestible intake
cattle.
Rev Vet Sci.
1970;
11
27-36
Reference Ris Wihthout Link
- 48
Birnbaum MJ.
Lipolysis: more than just a lipase.
J Cell Biol.
2003;
161
1011-1012
Reference Ris Wihthout Link
- 49
Escobar-Morreale HF, Rey FE, Escobar GM.
Thyroid hormones influence serum leptin concentrations in the rat.
Endocrinol.
1997;
138
4485-4488
Reference Ris Wihthout Link
- 50
Näslund E, Andersson I, Degerblad M, Kogner P, Kral JG, Rössner S, Hellström PM.
Associations of leptin, insulin resistance and thyroid function with long-term weight
loss in dieting obese men.
J Int Med.
2000;
248
299-308
Reference Ris Wihthout Link
- 51
Syed MA, Thompson MP, Pachucki J, Burmeister LA.
The effect of thyroid hormone on size of fat depots accounts for most of the changes
in leptin mRNA and serum levels in the rat.
Thyroid.
1999;
9
503-512
Reference Ris Wihthout Link
- 52
Wolfe BE, Jimerson DC, Orlova C, Mantozoros CS.
Effect of dieting on plasma leptin, soluble leptin receptor, adiponectin and resistin
levels in healthy volunteers.
Clin Endocrinol.
2004;
61
332-338
Reference Ris Wihthout Link
- 53
Brabant G, Horn R, Von Zur Mühlen A, Mayr B, Wurster U, Heidenreich F, Schnabel D, Grüters-Kieslich A, Zimmermann-Belsing T, Feldt-Rasmussen U.
Diabetologia.
2000;
43
438-442
Reference Ris Wihthout Link
- 54
Frederich RC, Löllmann B, Hamann A, Napolitano-Rosen A, Kahn BB, Lowell BB, Flier JS.
Expression of ob mRNA and its encoded protein in rodents – impact of nutrition and
obesity.
J Clin Invest.
1995;
96
1658-1663
Reference Ris Wihthout Link
- 55
Yoshida T, Monkawa T, Hayashi M, Saruta T.
Regulation of expression of leptin mRNA and secretion of leptin by thyroid hormone
in 3T3-L1 adipocytes.
Biochem Biophys Res Commun.
1997;
232
822-826
Reference Ris Wihthout Link
- 56
Luvizotto RAM, Conde SJ, Sibio MT, Nascimento AF, Lima-Leopoldo AP, Leopoldo AS, Padovani CR, Cicogna AC, Nogueira CR.
Administration of physiological levels of triiodothyronine increases leptin expression
in calorie-restricted obese rats, but does not influence weight loss.
Metabolism.
2010;
59
1-6
Reference Ris Wihthout Link
- 57
Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y.
Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.
Biochem Biophys Res Commun.
1999;
257
79-83
Reference Ris Wihthout Link
- 58
Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y.
Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2
diabetic patients.
Arterioscler Thromb Vasc Biol.
2000;
20
1595-1599
Reference Ris Wihthout Link
- 59
Yang WS, Jeng CY, Wu TJ, Tanaka S, Funahashi T, Matsuzawa Y, Wang JP, Chen CL, Tai TY, Chuang LM.
Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone,
increases plasma levels of adiponectin in type 2 diabetic patients.
Diabetes Care.
2002;
25
376-380
Reference Ris Wihthout Link
- 60
Hirose H, Kawai T, Yamamoto Y, Taniyama M, Tomita M, Matsubara K, Okazaki Y, Ishii T, Oguma Y, Takei I, Saruta T.
Effects of pioglitazone on metabolic parameters, body fat distribution, and serum
adiponectin levels in Japanese male patients with type 2 diabetes.
Metabolism.
2002;
51
314-317
Reference Ris Wihthout Link
- 61
Goldstein BJ, Scalia R.
Adipokines and vascular disease in diabetes.
Curr Diab Rep.
2007;
7
25-33
Reference Ris Wihthout Link
- 62
Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y.
Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling
through a cAMP-dependent pathway.
Circulation.
2000;
102
1296-1301
Reference Ris Wihthout Link
- 63
Aragao CN, Souza LL, Cabanelas A, Oliveira KJ, Pazos-Moura CC.
Effect of experimental hypo- and hyperthyroidism on serum adiponectin.
Metabolism.
2007;
56
6-11
Reference Ris Wihthout Link
- 64
Santini F, Marsili A, Mammoli C, Valeriano R, Scartabelli G, Pelosini C, Giannetti M, Centoni R, Vitti P, Pinchera A.
Serum concentrations of adiponectin and leptin in patients with thyroid dysfunctions.
J Endocrinol Invest.
2004;
27
RC5-RC7
Reference Ris Wihthout Link
- 65
Yaturu S, Prado S, Grimes SR.
Changes in adipocyte hormones leptin, resistin, and adiponectin in thyroid dysfunction.
J Cell Biochem.
2004;
93
491-496
Reference Ris Wihthout Link
- 66
Saito T, Kawano T, Saito T, Ikoma A, Namai K, Tamemoto H, Kawakami M, Ishikawa SE.
Elevations of serum adiponectin levels in Basedow disease.
Metabolism.
2005;
54
1461-1466
Reference Ris Wihthout Link
Correspondence
R. A. M. Luvizotto
Botucatu School of Medicine
University of São Paulo State
– UNESP
Distrito de Rubião Jr s/n
Botucatu SP CEP: 18618-000
Brazil
Phone: +55/14/3881 6213
Fax: +55/14/3881 6424
Email: reluvizotto@yahoo.com