**4.2. Resistin**

222 Thyroid Hormone

**4.1. Leptin** 

al. [84] showed by microarray that 19 genes of human white adipose tissue are regulated by thyroid hormone. These modulated genes give rise to proteins involved in transduction signal, lipid metabolism, apoptosis and inflammatory responses. The thyroid hormones inhibit proliferation and stimulate differentiation of adipocytes [85], regulate lipid metabolism by upregulation lipolytic enzymes expression, increase oxygen consumption

Since thyroid hormones affect adipose tissue metabolism, it is interesting to evaluate the relationship between thyroid hormones and adipokines in obese and weight loss, the focus

A potential interaction between leptin and thyroid hormones has been suggested since both

Leptin deficiency leads to severe obesity, however, in humans it's usually find high levels of leptin associated with leptin-resistance state [86-91]. Although thyroid function is usually normal in obese subjects, many studies have demonstrated that TSH levels are slightly increased in obese subjects [92-94]. Several studies have suggested that leptin influences TSH release, suggesting a regulatory role by leptin on thyroid axis at least in some conditions [35, 40, 95-101]. Thyroid hormones regulate the expression of several genes in human adipocyte [84], however, the role of thyroid hormones in leptin modulation remains

**Figure 3.** Adapted from Feldt-Rasmussem, 2007. Leptin can act on TRH or can directly influence T4 – T3 conversion, showing a regulatory role on thyroid axis. Despite contradictory data, thyroid hormone also regulates leptin levels increasing or decreasing depending on condition. TRH: thyroid release hormone; TSH: thyroid stimulating hormone; UCP3: uncoupling protein 3; T4: thyroxine; T3:

hormones are associated with body weight and energy expenditure regulation.

and modulate tissue sensitivity to other hormones [84].

**4. Thyroid hormone effect on adipokines in obesity** 

of discussion in next sections.

controversial (Figure 3).

triiodothyronine.

Resistin is strongly related to insulin resistance, showing increased resistin concentrations in obese and diabetic animals [46], and additionally it has been associated with inflammatory condition [119]. There is evidence that the hyperlipidic diet-induced obesity as well as leptin gene mutations are associated with high resistin circulating levels [120]. Resistin administered intraperitoneally increases plasma glucose and induces a hepatic insulin resistance. Other studies involving administration of resistin-recombinant promoted insulin resistance and reduced glucose transport stimulated by insulin, whereas administration of anti-resistin antibodies produced the opposite effect in rats [46]. Moreover, anti-resistin antibodies decrease blood glucose levels and improve the insulin sensitivity in obese rats [121, 122]. In mice with diet-induced obesity, immunoneutralization of resistin resulted in a 20% drop in blood glucose and improved insulin sensitivity as measured by insulin tolerance testing [46].

Resistin in humans is primarily produced in peripheral blood monocytes and its levels correlate with IL-6 concentrations [120], the question of its inflammatory role has been raised [123, 124], however the physiological role of resistin is far from clear and its role in obesity and insulin resistance and/or diabetes is controversial. Janke et al. [121] describes in

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 hormones and resistin in obesity.

Obesity and Weight Loss: The Influence of Thyroid Hormone on Adipokines 225

in body weight, body mass index and cholesterol serum levels after controlling for thyrotoxicosis. The lack of correlation between these parameters and serum adiponectin suggests that changes in body composition and lipid profile observed in hyperthyroidism are independent of adiponectin. In contrast, patients with hypothyroidism showed elevated cholesterol and triglycerides levels when compared to normal subjects. Thyroid function control was followed by a significant decrease in serum cholesterol and triglyceride concentrations. However no relationship between adiponectin and lipid profile before and after therapy was evidenced. Furthermore, after adjusting adiponectin levels for body mass index, no significant change was observed in patients with hyperand hypothyroidism, suggesting that thyroid hormones play a small role in adiponectin

An experimental study of rats with hyperthyroidism showed an important rise in serum adiponectin [133]. However, in contrast, Cabanelas et al. [134] show reduced adiponectin gene expression in inguinal explants of normal rats. Confirming this data Luvizotto et. al. [108] demonstrate that obese animals had decreased adiponectin serum levels when compared to control animals; and the administration of T3, interestingly, even diminishing the body fat mass, presented lower levels of adiponectin; showing that supraphysiological T3 doses alter adiponectin expression in obesity, suggesting that T3 may cause undesirable

*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

*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

levels modulation [128].

effects on adipose tissue.

**4.4. Others adipokines** 

TNF-α post-treatment levels and weight loss.

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 individuals [128].

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 mRNA gene expression in adipose tissue in obese rats.

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 influence resistin levels.

### **4.3. Adiponectin**

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 adiponectin has been well accepted.

Studies of a possible relationship between adiponectin and lipid metabolism changes associated with thyroid dysfunction are scarce. Hyperthyroid patients showed an increase in body weight, body mass index and cholesterol serum levels after controlling for thyrotoxicosis. The lack of correlation between these parameters and serum adiponectin suggests that changes in body composition and lipid profile observed in hyperthyroidism are independent of adiponectin. In contrast, patients with hypothyroidism showed elevated cholesterol and triglycerides levels when compared to normal subjects. Thyroid function control was followed by a significant decrease in serum cholesterol and triglyceride concentrations. However no relationship between adiponectin and lipid profile before and after therapy was evidenced. Furthermore, after adjusting adiponectin levels for body mass index, no significant change was observed in patients with hyperand hypothyroidism, suggesting that thyroid hormones play a small role in adiponectin levels modulation [128].

An experimental study of rats with hyperthyroidism showed an important rise in serum adiponectin [133]. However, in contrast, Cabanelas et al. [134] show reduced adiponectin gene expression in inguinal explants of normal rats. Confirming this data Luvizotto et. al. [108] demonstrate that obese animals had decreased adiponectin serum levels when compared to control animals; and the administration of T3, interestingly, even diminishing the body fat mass, presented lower levels of adiponectin; showing that supraphysiological T3 doses alter adiponectin expression in obesity, suggesting that T3 may cause undesirable effects on adipose tissue.
