**4.4. Others adipokines**

224 Thyroid Hormone

hormones and resistin in obesity.

mRNA gene expression in adipose tissue in obese rats.

individuals [128].

influence resistin levels.

adiponectin has been well accepted.

**4.3. Adiponectin** 

adipose tissue of obese individuals, although this adipokine has been identified, there was no correlation between resistin gene expression and their body weight, adiposity and insulin resistance. In contrast, high resistin levels are related to obesity and insulin resistance [46], and since body mass index has a possible association with thyroid hormones during periods of weight gain [125], could be establish a relationship between thyroid

Thyroid hormones appear to regulate resistin, at least in rats, however, in humans, studies on resistin levels and thyroid status have produced conflicting results. Some studies report that patients with hyperthyroidism have elevated resistin concentrations when compared with euthyroid control subjects [126]. Normalization of circulating thyroid hormones was accompanied by a significant decrease in resistin concentrations [126]. Others showed that hyperthyroid patients exhibit a significant decrease in resistin levels compared with euthyroid individuals. Normalization of circulating thyroid hormones levels was not accompanied by any significant change in resistin levels [127]. After adjusting the weight by the body mass index, the resistin levels of hyperthyroid patients were similar to euthyroid

Azza et al. [129] in their study with hypothyroid rats found an increase in body mass index without changes in resistin levels. On the other hand, Nogueiras et al. [130], found that adipose tissue resistin mRNA levels were increased in hypothyroid rats and decreased, to almost undetectable levels, in hyperthyroid rats. These data may help to explain previous findings showing a marked improvement in insulin resistance observed in obese rats after treatment with exogenous thyroid hormones [106]. Luvizotto et al. [108] reported that administration of T3 supraphysiological doses decreased resistin serum levels and ressitin

Data on the effect of thyroid hormones on resistin are scarce and controversial, so more studies are needed to elucidate the exact mechanism by which thyroid hormones may

The main target tissue and the precise mechanism of adiponectin action are not fully understood. The adiponectin activity is probably regulated at several levels, including gene expression, post-transcriptional modifications, oligomeric complexes formation, and proteolytic cleavage into smaller and perhaps more active fragments [131]. Some experimental models suggest that reduced adiponectin expression is associated with obesity and insulin resistance. Adiponectin expression may be activated during adipogenesis, but the feedback inhibition on its production may be involved in obesity development. It has been shown that adipogenic genes expression was suppressed during obesity and diabetes development in mice [132]. A negative correlation between obesity and circulating

Studies of a possible relationship between adiponectin and lipid metabolism changes associated with thyroid dysfunction are scarce. Hyperthyroid patients showed an increase *TNF-α* - Fruhbeck et al. [135] in their investigations revealed a narrow molecular link between TNF-α and obesity, verifying that TNF-α expression is increased in obesity, which in turn decreased insulin sensitivity, the same way of resistin. High-fat fed rodents showed significantly increased TNF-α expression and alteration in insulin signaling pathway *in vivo* [136]. Anti-TNF-α antibodies improves insulin sensitivity in obese rats, whereas TNFα deficient animals, even when subjected to high-fat diet, present themselves "protected" from obesity development and insulin resistance. TNF-α is a cytokine that may be involved in autoimmune thyroid disease development [137, 138]. Jiskra & Telicka [138] examined the relationship between thyroid function and cytokines, using patients with Graves' disease (characterized by hyperthyroidism), and patients with Hashimoto thyroiditis (disease characterized by hypothyroidism). The cytokine profile was assessed and patients with Hashimoto's thyroiditis present body mass index above the ideal level and TNF-α serum levels smaller than in patients with Graves' disease, who had body mass index within normal limits. Díez et al. [139] show that patients with hyperthyroidism before treatment present TNF-α serum levels higher than in control group, but hyperthyroidism treatment was accompanied by normalization of TNF-α levels. However TNF-α reduction was not observed in patients with hypothyroidism who have had the thyroid function normalized, despite a positive correlation between the TNF-α post-treatment levels and weight loss.

*IL-*6 - IL-6 levels are increased in obesity [140], and is also a marker of insulin resistance [141, 142]. According Nonogaki et al [143], metabolic impact produced by increased expression of IL-6 in the body fat deposits can be very importante in the obesity pathogenesis. The increase in IL-6 plasmatic could stimulate the hepatic synthesis of triacylglycerol, contributing to hypertriglyceridemia associated with visceral obesity. Data on relationship of thyroid hormones and IL-6 in obesity are scarce, but the association between reduction of T3 circulating levels and increasing pro-inflammatory cytokines, particularly IL-6, is described in the literature in both animals' models and human studies - septic patients and in patients with systemic inflammatory response [144, 145]. The acute subcutaneous administration of IL-6 (5 mg) in rats was associated with decrease in T4,T3 and TSH serum concentrations, while the T4/T3 ratio decreased, suggesting that T4 deiodination was not affected [144]. Changes in serum thyroid hormone concentrations could effectively be ascribed to IL-6, since they could be prevented by IL-6 preincubation with its neutralizing antibody [144]. The continuous IL-6 intraperitoneal infusion (15 mg/day for 7 consecutive days) in rats was associated with a transient decrease in serum T4 and TSH, although less than that caused by IL-1 [145]. In latter study, pro-TRH mRNA hypothalamic and pituitary TSH-b mRNA were unaffected by IL-6, suggesting that the effects of IL-6 on TSH might not necessarily be associated with a decreased synthesis of thyrotropin [145]. On the other hand, the observation that the intracerebroventricular IL-6 administration to rats was followed by a decrease in serum TSH and an increase in serum adrenocorticotropin (ACTH) concentrations, while these changes could be reproduced in hemipituitaries only for ACTH, but not for TSH, suggested that the action of IL-6 on TSH might be exerted predominantly at the hypothalamic levels [146]. Increased concentrations of cytokines, especially IL-6, are often found in nonthyroidal illness patients and correlate with changes in thyroid hormone concentrations [144].

Obesity and Weight Loss: The Influence of Thyroid Hormone on Adipokines 227

results demonstrated that adipocytes present different responses to thyroid hormones when considering *in vivo* and *in vitro* experiments. Other investigations have also demonstrated different *in vivo* and *in vitro* responses. The diverse *in vivo* and *in vitro* effects of thyroid hormones on PAI-1 gene expression regulation are not related to the inhibitory effect of T4 on thyroid-stimulating hormone (TSH) secretion, since the literature has not shown any relationship between TSH and PAI-1 serum concentration [157]. However, it could be suggested that the lower amount of thyroid hormone receptors and deiodinase present in white adipose tissue than in brain, liver, brown adipose tissue, and kidney may be involved in this process. In addition, the low blood flow in white adipose tissue in comparison to other tissue types [158] could contribute to hormone distribution *in vivo*, suggesting that lower amounts of T4 and T3 were achieved in adipocytes *in vivo* in comparison to the *in vitro* study. Thyroid hormones have different effects in relation to PAI-1 gene expression in adipocytes in the intact rat (*in vivo* study) and in cultured adipocytes (*in vitro* study). Further studies are required to better elucidate the diverse *in vivo* and *in vitro* effects of thyroid

*ASP* - In a number of studies, ASP has been demonstrated to be increased in obesity, diabetes and cardiovascular disease [159-161]. Plasma ASP levels correlate positively with body mass index, as well as with plasma lipids. Study using culture of human adipocytes revealed increased secretion of chylomicrons induced by ASP [162]. There is evidence that circulating lipids also stimulate the expression of ASP after drinking large quantities of these nutrients [163]. There is no data available regarding the effect of thyroid hormones on ASP

*RAS*- Adipose tissue synthesizes and secretes the major components of RAS [164]. There is evidence for overactivation of adipose tissue RAS in obesity in rodents [165], and for a positive correlation between adipose tissue angiotensinogen levels and BMI in humans [166]. Also Ang II secretion from adipose tissue is increased in obese, but not lean, individuals [167]. Increased production of angiotensinogen with excess gain in white adipose tissue contributes to glucose intolerance development, insulin resistance, cardiovascular and renal diseases [76, 168, 169]. In addition, increased RAS activity contributes to inflammation in fat tissue [170]. The interaction of RAS with other adipokines also contributes to the development of metabolic syndrome. Ang II appears to stimulate leptin production by adipocytes [76]; which in turn, hyperleptinemia may further hyperactivity of RAS by stimulating renin release by the kidney. Ang II may also regulate negatively adipocyte production of adiponectin in both rodents and humans [171, 172]. Thyroid hormones are important regulators of cardiac and renal functions while RAS components act systemically and locally in individual organs also to control cardiovascular and renal functions. Several studies have implicated the systemic and local RAS in the mediation of functional and structural changes in cardiovascular and renal tissues due to abnormal thyroid hormone levels [173, 174]. Thyroid hormones also appear to stimulate

hormone on adipocytes PAI-1 gene expression [156].

expression and synthesis of RAS components [175-177].

levels in obesity.

*MCP-1* - Expression in adipose tissue and plasma MCP-1 levels have been found to correlate positively with the degree of obesity [7, 147-149]. Elevated circulating levels of MCP-1 as well as MCP-1 mRNA have been reported in obese mice [149, 150]. The possibility that MCP-1 formation in adipose tissue is due to macrophage infiltration must be considered since obesity is associated with various degrees of macrophage accumulation in adipose tissue [7, 147]. No data on this adipokines and thyroid hormone have been published.

*PAI-1* - Adipose tissue PAI-1 gene expression and serum concentration have been reported in several pathological conditions, such as obesity, hyperinsulinemia, and hyperglycemia [151, 152]. The thyroid hormones T4 and T3 also have cardiovascular effects, probably through the regulation of circulating clotting proteins and fibrinolytic activity [153]; however, the mechanisms leading to cardiovascular and thromboembolytic diseases in thyroid dysfunction are controversial. Some reports have described an increase in serum PAI-1 concentration in hyperthyroidism, whereas others did not detect any differences [154, 155]. Biz, et al. [158] determined the effects of *in vivo* treatment of rats with the thyroid hormone T4 on gene expression and the serum concentration of PAI-1. Additionally, the effects of T3 and T4 on PAI-1 gene expression in 3T3-L1 adipocytes were also evaluated. The results demonstrated that adipocytes present different responses to thyroid hormones when considering *in vivo* and *in vitro* experiments. Other investigations have also demonstrated different *in vivo* and *in vitro* responses. The diverse *in vivo* and *in vitro* effects of thyroid hormones on PAI-1 gene expression regulation are not related to the inhibitory effect of T4 on thyroid-stimulating hormone (TSH) secretion, since the literature has not shown any relationship between TSH and PAI-1 serum concentration [157]. However, it could be suggested that the lower amount of thyroid hormone receptors and deiodinase present in white adipose tissue than in brain, liver, brown adipose tissue, and kidney may be involved in this process. In addition, the low blood flow in white adipose tissue in comparison to other tissue types [158] could contribute to hormone distribution *in vivo*, suggesting that lower amounts of T4 and T3 were achieved in adipocytes *in vivo* in comparison to the *in vitro* study. Thyroid hormones have different effects in relation to PAI-1 gene expression in adipocytes in the intact rat (*in vivo* study) and in cultured adipocytes (*in vitro* study). Further studies are required to better elucidate the diverse *in vivo* and *in vitro* effects of thyroid hormone on adipocytes PAI-1 gene expression [156].

226 Thyroid Hormone

in thyroid hormone concentrations [144].

have been published.

IL-6 in the body fat deposits can be very importante in the obesity pathogenesis. The increase in IL-6 plasmatic could stimulate the hepatic synthesis of triacylglycerol, contributing to hypertriglyceridemia associated with visceral obesity. Data on relationship of thyroid hormones and IL-6 in obesity are scarce, but the association between reduction of T3 circulating levels and increasing pro-inflammatory cytokines, particularly IL-6, is described in the literature in both animals' models and human studies - septic patients and in patients with systemic inflammatory response [144, 145]. The acute subcutaneous administration of IL-6 (5 mg) in rats was associated with decrease in T4,T3 and TSH serum concentrations, while the T4/T3 ratio decreased, suggesting that T4 deiodination was not affected [144]. Changes in serum thyroid hormone concentrations could effectively be ascribed to IL-6, since they could be prevented by IL-6 preincubation with its neutralizing antibody [144]. The continuous IL-6 intraperitoneal infusion (15 mg/day for 7 consecutive days) in rats was associated with a transient decrease in serum T4 and TSH, although less than that caused by IL-1 [145]. In latter study, pro-TRH mRNA hypothalamic and pituitary TSH-b mRNA were unaffected by IL-6, suggesting that the effects of IL-6 on TSH might not necessarily be associated with a decreased synthesis of thyrotropin [145]. On the other hand, the observation that the intracerebroventricular IL-6 administration to rats was followed by a decrease in serum TSH and an increase in serum adrenocorticotropin (ACTH) concentrations, while these changes could be reproduced in hemipituitaries only for ACTH, but not for TSH, suggested that the action of IL-6 on TSH might be exerted predominantly at the hypothalamic levels [146]. Increased concentrations of cytokines, especially IL-6, are often found in nonthyroidal illness patients and correlate with changes

*MCP-1* - Expression in adipose tissue and plasma MCP-1 levels have been found to correlate positively with the degree of obesity [7, 147-149]. Elevated circulating levels of MCP-1 as well as MCP-1 mRNA have been reported in obese mice [149, 150]. The possibility that MCP-1 formation in adipose tissue is due to macrophage infiltration must be considered since obesity is associated with various degrees of macrophage accumulation in adipose tissue [7, 147]. No data on this adipokines and thyroid hormone

*PAI-1* - Adipose tissue PAI-1 gene expression and serum concentration have been reported in several pathological conditions, such as obesity, hyperinsulinemia, and hyperglycemia [151, 152]. The thyroid hormones T4 and T3 also have cardiovascular effects, probably through the regulation of circulating clotting proteins and fibrinolytic activity [153]; however, the mechanisms leading to cardiovascular and thromboembolytic diseases in thyroid dysfunction are controversial. Some reports have described an increase in serum PAI-1 concentration in hyperthyroidism, whereas others did not detect any differences [154, 155]. Biz, et al. [158] determined the effects of *in vivo* treatment of rats with the thyroid hormone T4 on gene expression and the serum concentration of PAI-1. Additionally, the effects of T3 and T4 on PAI-1 gene expression in 3T3-L1 adipocytes were also evaluated. The *ASP* - In a number of studies, ASP has been demonstrated to be increased in obesity, diabetes and cardiovascular disease [159-161]. Plasma ASP levels correlate positively with body mass index, as well as with plasma lipids. Study using culture of human adipocytes revealed increased secretion of chylomicrons induced by ASP [162]. There is evidence that circulating lipids also stimulate the expression of ASP after drinking large quantities of these nutrients [163]. There is no data available regarding the effect of thyroid hormones on ASP levels in obesity.

*RAS*- Adipose tissue synthesizes and secretes the major components of RAS [164]. There is evidence for overactivation of adipose tissue RAS in obesity in rodents [165], and for a positive correlation between adipose tissue angiotensinogen levels and BMI in humans [166]. Also Ang II secretion from adipose tissue is increased in obese, but not lean, individuals [167]. Increased production of angiotensinogen with excess gain in white adipose tissue contributes to glucose intolerance development, insulin resistance, cardiovascular and renal diseases [76, 168, 169]. In addition, increased RAS activity contributes to inflammation in fat tissue [170]. The interaction of RAS with other adipokines also contributes to the development of metabolic syndrome. Ang II appears to stimulate leptin production by adipocytes [76]; which in turn, hyperleptinemia may further hyperactivity of RAS by stimulating renin release by the kidney. Ang II may also regulate negatively adipocyte production of adiponectin in both rodents and humans [171, 172]. Thyroid hormones are important regulators of cardiac and renal functions while RAS components act systemically and locally in individual organs also to control cardiovascular and renal functions. Several studies have implicated the systemic and local RAS in the mediation of functional and structural changes in cardiovascular and renal tissues due to abnormal thyroid hormone levels [173, 174]. Thyroid hormones also appear to stimulate expression and synthesis of RAS components [175-177].
