**6. The use of TRβ analogues**

230 Thyroid Hormone

decreases with weight loss, thereby improving insulin sensitivity [135, 198]. After weight loss there is a decrease of macrophages number in adipose tissue [199], this can lead to decreased TNF-α levels, since both adipose tissue and macrophages produce this cytokine. There are few studies correlating the thyroid status with TNF-α levels in weight loss. Patients with HIV tend to lose weight and in some cases it is observed a decrease in T3 levels accompanied by increased TNF-α levels, when these individuals are compared to patients with HIV with normal T3 levels. These results corroborate to other study linking the sick

euthyroid syndrome to high TNF-α levels in cachectic patients with HIV [200].

**Figure 4.** Thyroid hormone may modulate adipokines concentration by regulating adipose tissue metabolism by, *i.e.*, increasing lipid oxidation leading to body fat decreased. The exact influence of

*IL-6* - IL-6 levels decrease with weight loss [140-142]. The intracerebroventricular administration of this cytokine can decrease body fat [201]. Association studies between thyroid hormones and IL-6 in weight loss are scarce, but studies in critically patients demonstrated a direct association between decreased T3 levels and high IL-6 plasma levels, demonstrating that approximately 28% of T3 fall could be directly related to increased IL-6 [202]. In another study, of 270 patients admitted to intensive care unit, serum T3, T4 and IL-6 were measured and again was observed a negative correlation between T3 and T4 levels and IL-6 levels, demonstrating that this cytokine could be an important factor associated with

*MCP-1* - Chronic inflammation associated with obesity exists in dogs, and it is evident that weight loss decreases this inflammation as observed by decreasing MCP-1 after weight loss [204]. In agreement, Kanda et al. [205] demonstrated that MCP-1 deficient mice have reduced adipose tissue macrophage infiltration. Few studies correlate weight loss and MCP-1 levels, and no data was found regarding weight loss, MCP-1 and thyroid association.

*PAI-1* - Weight loss secondary to calorie restriction is associated with reduced PAI-1 activity in adults [206, 207]. However, in children no significant change in PAI-1 levels was observed in 43 obese children after a physical training program [208]. This may be explain by the increase in fibrinolytic activity due to a decrease in PAI-1 antigen levels in obese children after weight loss, and a significant positive correlation was observed between variations in

thyroid hormone on adipokines remains unclear.

decreased circulating thyroid hormones levels [203].

Thyroid hormone analogues, termed thyromimetics, are molecules with activate signaling pathway property similar to thyroid hormones, sometimes with tissue specificity or by activating a singular pathway stimulated by thyroid hormones, other with less effect, but even with a way close to thyroid hormones. The thyromimetics have a great pharmaceutical potential since they present certain specificity as intracellular signaling that stimulate and thus may have a tissue specific action. However, only the past 20 years, with increasing

resolution of three-dimensional models, docking experiments and crystallography models the specificity of thyromimetics has been revealed.

Obesity and Weight Loss: The Influence of Thyroid Hormone on Adipokines 233

[242]. The same results were observed with KB-141 use, but with a subtle increase in heart rate. Contributing to cholesterol serum levels reduction by GC-1 is the increased SR-BI expression, a receptor that promotes cholesterol uptake in the liver, stimulating the bile acids production [243]. Deleterious effects absence of GC-1 on cardiac structure and function [244], skeletal muscle and bone mass [245] suggests that GC-1 has potential therapeutic use

Started studies during the mid-1990s, N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy) phenyl] oxamic acid (CGS-23425) was a potent ability to decrease cholesterol in rats and dogs at dose 25 times higher than the minimum for producing lipid lowering effects [247]. In hypercholesterolemic rats, CGS-23425 had the desired effects of decreasing serum LDL and increased apoA1, with a corresponding increase in apoA1 gene transcription by TR-β1

A thyroid hormone analogue currently in phase II clinical trial is the 3.5 diiodothyropropionic acid (DITPA), with affinity equivalent between TR-α1 and β1 but with 100 times less affinity than T3 [249]. In hypothyroid rats, DITPA improved cardiac performance with half the chronotropic effect and less metabolic stimulation than levothyroxine [250]. In normal volunteers, DITPA does not affect the heart rate or blood pressure, while the serum cholesterol and triglycerides were significantly decreased [251]. Observations have shown that DIPTA exerts its action by stimulating nongenomic pathways stimulated by T3 as the αVβ3 integrin receptor, activating the MAPK cascade and causing similar effects to those seen with GC-1, leading to angiogenesis, indicating that some cardiac

Although there are few studies on thyromimetics and adipokines, studies on obesity and lipid lowering show interesting results. Other compounds have been studied as thyroid hormone natural metabolic intermediates: 3-iodothyronamine (T1AM) showed effects on cardiac output, heart hate and decreased body temperature with neuroprotective action; Diiodothyronine-3.5 (T2) with effects such as increased lipid peroxidation and fatty acids oxidation, among others; 3,3 ', 5'-triiodothyronine (rT3) able to initiate actin polymerization; triiodothyroacetic acid (Triac) that increases the metabolic rate and thermogenesis, and one of the few identified analogues able to increase leptin secretion [246]. Like thyromimetics, these natural metabolites, collectively, show body weight and fat mass reduction, while thyromimetics are more specific to reduce cholesterol serum levels, but both have effects saving cardiac activity. However, before they are used in large scale, attention should be paid to non-selectivity presented by natural metabolites, and for TSH suppression showed by thyromimetics, which may lead to undesirable tissue hypothyroidism. Thus, the tissue specificity and selectivity for TR brings a good perspective for thyromimetics, however there

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

for metabolic disorders such as obesity and hyperlipidemia [246].

effects may be caused by nongenomic pathway activation [252].

is still a long way from its use as therapeutic agent.

**7. Final considerations** 

selectively [248].

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 TSH release.

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 some details of their actions.

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 [242]. The same results were observed with KB-141 use, but with a subtle increase in heart rate. Contributing to cholesterol serum levels reduction by GC-1 is the increased SR-BI expression, a receptor that promotes cholesterol uptake in the liver, stimulating the bile acids production [243]. Deleterious effects absence of GC-1 on cardiac structure and function [244], skeletal muscle and bone mass [245] suggests that GC-1 has potential therapeutic use for metabolic disorders such as obesity and hyperlipidemia [246].

Started studies during the mid-1990s, N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy) phenyl] oxamic acid (CGS-23425) was a potent ability to decrease cholesterol in rats and dogs at dose 25 times higher than the minimum for producing lipid lowering effects [247]. In hypercholesterolemic rats, CGS-23425 had the desired effects of decreasing serum LDL and increased apoA1, with a corresponding increase in apoA1 gene transcription by TR-β1 selectively [248].

A thyroid hormone analogue currently in phase II clinical trial is the 3.5 diiodothyropropionic acid (DITPA), with affinity equivalent between TR-α1 and β1 but with 100 times less affinity than T3 [249]. In hypothyroid rats, DITPA improved cardiac performance with half the chronotropic effect and less metabolic stimulation than levothyroxine [250]. In normal volunteers, DITPA does not affect the heart rate or blood pressure, while the serum cholesterol and triglycerides were significantly decreased [251]. Observations have shown that DIPTA exerts its action by stimulating nongenomic pathways stimulated by T3 as the αVβ3 integrin receptor, activating the MAPK cascade and causing similar effects to those seen with GC-1, leading to angiogenesis, indicating that some cardiac effects may be caused by nongenomic pathway activation [252].

Although there are few studies on thyromimetics and adipokines, studies on obesity and lipid lowering show interesting results. Other compounds have been studied as thyroid hormone natural metabolic intermediates: 3-iodothyronamine (T1AM) showed effects on cardiac output, heart hate and decreased body temperature with neuroprotective action; Diiodothyronine-3.5 (T2) with effects such as increased lipid peroxidation and fatty acids oxidation, among others; 3,3 ', 5'-triiodothyronine (rT3) able to initiate actin polymerization; triiodothyroacetic acid (Triac) that increases the metabolic rate and thermogenesis, and one of the few identified analogues able to increase leptin secretion [246]. Like thyromimetics, these natural metabolites, collectively, show body weight and fat mass reduction, while thyromimetics are more specific to reduce cholesterol serum levels, but both have effects saving cardiac activity. However, before they are used in large scale, attention should be paid to non-selectivity presented by natural metabolites, and for TSH suppression showed by thyromimetics, which may lead to undesirable tissue hypothyroidism. Thus, the tissue specificity and selectivity for TR brings a good perspective for thyromimetics, however there is still a long way from its use as therapeutic agent.
