**7. Final considerations**

232 Thyroid Hormone

TSH release.

some details of their actions.

resolution of three-dimensional models, docking experiments and crystallography models

Thyroid hormone is one of the most responsible for metabolism controlling and cell oxygen consumption, affecting growth, cell differentiation and homeostasis control [229]. The thyroid hormone also has specific functions depending on tissue: in liver, controlling lipid metabolism [230-232]; in heart, regulating the calcium handling and the heart rate [233]. As for lipid deposits, the thyroid hormone acts in brown adipose tissue by controlling heating and adaptive thermogenesis during rest [234]. Under high hormone levels conditions in the organism, such as hyperthyroidism, there is an increase in metabolic rate with consequent weight loss and decrease cholesterol serum levels, desirable conditions for metabolic diseases treatment such as obesity [235] and hyperlipidemia [230-232]. In this context, the possible specificity through thyroid homone analogues may lead to desirable effects on adipokines release control and obesity, without the undesirable symptoms on heart or on

Thyromimetics can be seen as thyroid hormone derivative or its metabolites derivative. Studies on the direct influence of these analogues on adipokines levels are scarce, but the tissue selectivity shown may be interesting in the study of non thyroid diseases, mainly involving the lipid rate control in adipose tissue and decreased cholesterol by the liver. This selectivity in many cases is related to action pathway stimulate by thyromimetics. Some of them may have actions in liver and adipose tissue through its selective binding to TR-β1, while not lead to effects such as tachycardia since there is no selectivity for the TR-α1 (most expressed isoform in the heart). Thus we can highlight some known thyromimetics and

The first developed analogue, in the mid-1980s, was 3,5-dibromo-3-pyridazinone-Lthyronine (L-94901) present 50% of binding T3 to TRs in liver, and only 1.3% effective for cardiac TRs [236, 237]. L-94901 showed an increase of oxygen overall consumption and a reduction in cholesterol serum levels in animal models submitted to low dose, sufficient to prevent cardiotoxic effects, however, also led to lower TSH, T4 and T3 plasma levels [236].

An analogue selectivity-related to TR-β1 is 3,5-Dichloro-4-[(4-hydroxy-3-isopropylphenoxy) phenyl] acetic acid (KB-141), with 10-fold greater ability to reduce the cholesterol rate than increase heart rate [238, 239], stimulating metabolic rate and oxygen consumption [240]. Eprotirome (KB2115) is a thyroid hormone analogue that has a low uptake by non-hepatic tissues. It has preferential selectivity for the TRβ, leading to decreased total cholesterol, LDL and apolipoprotein B levels without apparent side-effects. It showed good results in hypercholesterolemia treatment and associated with statin was effective in reducing atherogenic lipoproteins levels without extra-hepatics effects of thyroid hormone [241].

One of the most widely studied thyroid hormone analogues is 3,5-dimethyl-4-[(4'-hydroxy-3'-isopropylbenzyl)-phenoxy] acetic acid (CG-1), with selectivity for TRβ 10-fold greater than for TR-α. Hypercholesterolemic rats models treated with GC-1 showed decrease in cholesterol, LDL and triglyceride serum levels, without significantly altering heart function or regulated-thyroid hormone gene expression as MHC-HT and α, β-MHC and SERCA2

the specificity of thyromimetics has been revealed.

Adipose tissue produces a wide range of biological active substances, named adipokines, involved in glucose metabolism, lipid metabolism, inflammation, coagulation, blood pressure, and feeding behavior, thus affecting metabolism and function of many organs and tissues including muscle, liver, vasculature, and brain. Obesity cause imbalance in the adipokines production, while the weight loss are able to normalize these changes. In obese, the stabilization of weight loss even in calorie restricted diet has been attributed to the decrease in serum T3 concentrations, leading to a reduction in metabolic rate. Because of this, and despite not being accepted as an obesity treatment, the administration of thyroid hormones, in isolation or in association with hypocaloric diets, is sometimes used illicitly. The thyroid hormones regulate the energetic balance and act on the adipokines, regulating several genes in adipose tissue. However, the available data on the effects of thyroid hormone on adipokines in obesity or weight loss are conflicting. A clear association has not yet been established between in obesity and calorie restriction in obesity and the effect of thyroid hormone on adipokines, requiring further studies. Despite studies of TRβ analogs show good results, the direct influence of these analogues on adipokines levels are scarce. More research is needed to fully elucidate the exact mechanism of thyroid hormone and its analogues on adipokines in obesity and weight loss.

Obesity and Weight Loss: The Influence of Thyroid Hormone on Adipokines 235

[9] Rasouli N and Kern P A 2008 Adipocytokines and the metabolic complications of

[10] Fontana L 2009 Neuroendocrine factors in the regulation of inflammation: excessive

[12] Kennedy G C 1953 The role of depot fat in the hypothalamic control of food intake in

[13] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L and Friedman J M 1994 Positional cloning of the mouse obese gene and its human homologue *Nature* 372 425-32 [14] Janeckova R 2001 The role of leptin in human physiology and pathophysiology *Physiol* 

[15] Havel P J 2001 Peripheral signals conveying metabolic information to the brain: shortterm and long-term regulation of food intake and energy homeostasis *Exp Biol Med* 

[16] Aronne L J and Thornton-Jones Z D 2007 New targets for obesity pharmacotherapy *Clin* 

[17] Klein I and Ojamaa K 2001 Thyroid hormone and the cardiovascular system *N Engl J* 

[18] Baranowska B, Radzikowska M, Wasilewska-Dziubinska E, Roguski K and Borowiec M 2000 Disturbed release of gastrointestinal peptides in anorexia nervosa and in obesity

[19] Ramacciotti C E, Coli E, Paoli R, Marazziti D and Dell'Osso L 2003 Serotonergic activity measured by platelet [3H]paroxetine binding in patients with eating disorders

[20] Kaye W H, Barbarich N C, Putnam K, Gendall K A, Fernstrom J, Fernstrom M, McConaha C W and Kishore A 2003 Anxiolytic effects of acute tryptophan depletion in

[21] Metwally M, Ledger W L and Li T C 2008 Reproductive endocrinology and clinical

[22] Lopez D, Abisambra Socarras J F, Bedi M and Ness G C 2007 Activation of the hepatic LDL receptor promoter by thyroid hormone *Biochim Biophys Acta* 1771 1216-25 [23] Ladenson P W, McCarren M, Morkin E, Edson R G, Shih M C, Warren S R, Barnhill J G, Churby L, Thai H, O'Brien T, Anand I, Warner A, Hattler B, Dunlap M, Erikson J and Goldman S 2010 Effects of the thyromimetic agent diiodothyropropionic acid on body weight, body mass index, and serum lipoproteins: a pilot prospective, randomized,

[24] Banks W A and Lebel C R 2002 Strategies for the delivery of leptin to the CNS *J Drug* 

[25] Niswender K D and Schwartz M W 2003 Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities *Front* 

[26] Schwartz M W, Woods S C, Porte D, Jr., Seeley R J and Baskin D G 2000 Central nervous

anorexia nervosa *Int J Eat Disord* 33 257-67; discussion 68-70

aspects of obesity in women *Ann N Y Acad Sci* 1127 140-6

controlled study *J Clin Endocrinol Metab* 95 1349-54

system control of food intake *Nature* 404 661-71

obesity *J Clin Endocrinol Metab* 93 S64-73

the rat *Proc R Soc Lond B Biol Sci* 140 578-96

*Res* 50 443-59

*Med* 344 501-9

*(Maywood)* 226 963-77

*Pharmacol Ther* 81 748-52

*Diabetes Obes Metab* 2 99-103

*Psychiatry Res* 118 33-8

*Target* 10 297-308

*Neuroendocrinol* 24 1-10

adiposity and calorie restriction *Exp Gerontol* 44 41-5

[11] Miner J L 2004 The adipocyte as an endocrine cell *J Anim Sci* 82 935-41
