**3. Adipokines and thyroid hormones**

220 Thyroid Hormone

nuclear factor kappaB [65].

degradation [64]. Both TNF-α and triiodothyronine are involved in the tissue homeostasis maintenance of the anterior pituitary gland, however, triiodothyronine inhibit the signaling cascade that TNF-α promotes on this tissue in signaling pathways affecting MAPK p38 and

*Interleukin-6* (IL-6) – IL-6 is also a cytokine with pro-inflammatory effect in acute responses and action on carbohydrates and lipids metabolism [66, 67]. IL-6 circulates in glycosylated form ranging from 22 to 27 kDa. Its receptor (IL-6R) is homologous to the leptin receptor and exists in two isoforms, a membrane-bound and soluble. The infusion of IL-6 near physiological doses, in healthy humans, increase lipolysis independently of catecholamines, glucagon and insulin modulation [68], indicating IL-6 as an important factor in lipid metabolism. As TNF-α, it inhibits the LLP and increases free fatty acids and glycerol release. Furthermore, the increased expression may be related to leptin suppression and stimulation of C-reactive protein production, as well as in reducing IRS-1 and GLUT-4 expression in the liver and muscle [66]. IL-6 is secreted by adipocytes and macrophages, which are responsible for 30% of its secretion [67]. Catecholamines can stimulate IL-6 expression via β2-and β3-adrenoceptors in adipose tissue, when in high concentrations [69]. The IL-6 central administration increases energy expenditure and decreases body fat in rodents. Also, transgenic mice with IL-6 overexpressed showed generalized growth deficiency and reduced body mass, however, IL-6 deficient mice develop obesity and metabolic abnormalities, suggesting that IL-6 may prevent, rather than cause these conditions [70].

*Monocyte chemotactic protein-1* (MCP-1) – MCP-1 is a chemokine and a member of the small inducible cytokine family, which plays a role in the recruitment of monocytes and T lymphocytes to sites of injury and infection. Its main receptor is the chemokine CC motif receptor (CCR) 2 that is expressed in various cell types including adipocytes, skeletal muscle cells and macrophages. MCP-1 was first described as a secretory product of monocytes and endothelial cells with a role in atherosclerosis. MCP-1, acting through its receptor CCR2, is now thought to play a central role in the recruitment of monocytes to atherosclerotic lesions and in the development of intimal hyperplasia after arterial injury. Owing to their crucial roles in monocyte recruitment in vascular and nonvascular diseases, MCP-1 and CCR2 have become important therapeutic targets in cardiovascular research. Furthermore, MCP-1 plays a role in inflammation in insulin-responsive tissues. As for skeletal muscle, MCP-1 is increased during myopathies and can be induced by interferon-gamma. Recently, MCP-1

*Plasminogen activator inhibitor* (PAI)-1 – Adipocytes can secrete many proteins in hemostasis and fibrinolytic system as PAI-1 [72]. PAI-1 is a member of the serine protease inhibitor family and is the primary inhibitor of fibrinolysis by inactivating urokinase-type and tissuetype plasminogen activator. PAI-1 has also been implicated in a variety of other biological processes including angiogenesis and atherogenesis. PAI-1 is expressed by many cell types within adipose tissue including adipocytes [3]. PAI-1 expression and secretion are greater in visceral adipose tissue relative to subcutaneous adipose tissue [54]. PAI-1 promotes thrombi formation and unstable atherogenic plaque rupture, and change the fibrinolytic balance by

has been attributed an additional role in the pathophysiology of obesity [71].

The thyroid gland mainly produces the thyroid hormones T3 and T4. However, also produces small amounts of other iodothyronines as reverse T3 and 3,5-diiodo-L-thyronine. This gland is part of hypothalamic-pituitary-thyroid axis. Thyroid hormones secretion is regulated by the classical mechanism of negative feedback; briefly, thyroid releasing hormone (TRH), produced predominantly by neurons of the paraventricular nucleus in the hypothalamus, stimulates the release of thyroid stimulating hormone (TSH) in pituitary and this in turn, stimulates the synthesis and release of thyroid hormones. The increase in thyroid hormones serum concentrations inhibit the production of both TRH and TSH, leading to decreased thyroid function. The subsequent decrease in thyroid hormones serum levels, in turn, stimulates TRH and TSH, again increasing the concentration of hormones [79]. Thyroid hormones act in the body through the coupling to its receptor (TR) and (TR). The thyroid hormone receptors (TRs), members of the superfamily of nuclear receptors interact with a specific DNA sequence, called responsive element in the promoter region of target gene and regulates gene transcription [80]. Generally, TRs are repressors in the absence of binding T3 and transcriptional activators in its presence [81].

Although the thyroid hormones are essential for the survival [37], thyroid function disorder leads to changes in metabolic parameters, for example, thyroid hormone excess is associated with weight loss and reduced muscle and fat mass [82] , showing that thyroid hormones play a central role in regulating the adipose tissue metabolism [83]. Furthermore, Viguerie et 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 and modulate tissue sensitivity to other hormones [84].

Obesity and Weight Loss: The Influence of Thyroid Hormone on Adipokines 223

Studies with rodents indicate that thyroid hormones exert a negative influence on serum leptin concentrations [102-105]. Syed et al. [106] also found similar results, but report that thyroid hormones influence leptin levels indirectly through the regulation of fat mass. Wang et al. [107] reported that although leptin and thyroid hormones might affect the same pathways to regulate energy metabolism, the leptin effects on metabolism are not dependent upon the presence of thyroid hormones. In agreement, Luvizotto et al. [108] reported that T3 administration in obese rats promotes weight loss and diminishes serum levels and gene expression of leptin and other adipokines. Contrary to these results, Yoshida et al. [109] founds increased leptin mRNA levels in 3T3-L1 cell cultures treated with T3 at

Obese human subjects have high serum leptin levels as leptin concentrations are directly proportional to body fat mass, more specifically to adipocyte volume [110, 111]. Regarding to thyroid hormones, there is indications that human obesity is usually associated with increased TSH and T3 levels [92, 112]. As in rats, studies with humans reached to controversial results about the effect of thyroid hormones over leptin concentrations. In fact, human studies present more difficulties in terms of controlling variables as patient characteristics, treatments and method for measuring leptin levels and body composition. In hypothyroid subjects serum leptin was found to be increased [83, 113], decreased [114, 115] or unchanged [116, 117] when compared with euthyroid subjects. The same controversial

These conflicting results might be explained by the existence of many factors influencing leptin levels and thyroid hormones, and more studies are needed to fully understand the

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

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

results are found in studies with hyperthyroid subjects [83, 113, 115-118].

physiological and supraphysiological doses.

relationship between leptin and thyroid hormones.

**4.2. Resistin** 

tolerance testing [46].

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 of discussion in next sections.
