**2.4. Others adipokines**

218 Thyroid Hormone

**2.2. Resistin** 

glucose uptake [46].

be determined [3].

**2.3. Adiponectin** 

and has biological activity [53].

correlation between plasma adiponectin and fat mass [52].

Resistin is a polypeptide at approximately 12kDa and belongs to proteins family with cysteine-rich C-terminal domain call resistin-like molecules, which are identical to those found in inflammatory zone family, giving to resistin the alias FIZZ3 [44]. Its expression is 15 fold higher in visceral adipose tissue when compared to subcutaneous adipose tissue, in rodents [44], but it is also expressed in human macrophages [45]. Its name is due to the resistin presents a significant role in obesity-associated insulin resistance [46] and its molecular structure is very similar to adiponectin. Resistin production increases with food

Resistin promotes insulin resistance by increasing hepatic gluconeogenesis, and presenting rapid effect on this tissue [47]. Other *in vivo* study also found effects of administration and neutralization of resistin on glucose tolerance in skeletal muscle and adipose tissue, indicating resistin action also in these tissues by negative modulation of insulin signaling on

Regarding the specific body fat deposits, resistin expressions 2-3 fold higher is found in visceral adipose tissue, followed by subcutaneous, abdominal and gluteal-femoral subcutaneous. Its expression is 3 fold higher in preadipocytes compared with mature

Resistin deficient mice have weight and fat mass similar to wild-type mice, even when high-fat fed. However, resistin deficient mice significantly improved fasting glucose levels in control diet and improved glucose tolerance in high-fat diet. Insulin sensitivity is unaffected. The improvement in glucose homeostasis in resistin deficient mice is associated with decreased hepatic gluconeogenesis. Whereas these data support a resistin role in glucose homeostasis during fasting in rodents, a similar role in humans remains to

Adiponectin, also known as ACRP 30 (adipocyte complement related protein of 30kDa), apM1 (adipose most abundant gene transcript 1), AdipQ or GBP28 (gelatin binding protein of 28 kDa) [49-52], is a protein exclusively expressed in differentiated adipocytes and circulates in high levels in the blood [53], presenting greater expression in subcutaneous adipose tissue than in visceral adipose tissue [54]. Unlike other factors secreted by adipose tissue, adiponectin acts as a protective factor for cardiovascular disease and increases insulin sensitivity. It is an approximately 30 kDa polypeptide that shows high homology with collagen VIII and X, and complement component C1q. A proteolytic cleavage product containing the globular domain of adiponectin circulate in physiologically significant levels

Except for cases of severe malnutrition [55] and in neonates [56], there is a strong negative

intake and obesity, and decreases in the presence of PPAR-gamma ligands [47].

adipocytes, also functioning as a potential regulator of adipogenesis [48].

*Tumor Necrose Factor - alpha* (TNF-α) – TNF-α is a cytokine expressed by adipocytes and stromovascular cells, with higher expression in subcutaneous adipose tissue compared to visceral adipose tissue, acting directly on adipocytes, promoting apoptosis induction, lipogenesis inhibition, by inhibiting lipoprotein lipase (LLP), GLUT-4 and the acetyl CoA synthetase expressions, as well as increased lipolysis, therefore exerting an important regulatory role in fat accumulation in adipose tissue [61, 62]. TNF-α is a transmembrane protein of 26 kDa, which, after being cleaved generates a portion of 17-kDa, which is biologically active and exerts its effects through TNF- receptor type I and II. It is a cytokine initially described as an endotoxin-induced factor causing necrosis in tumors. The ability of TNF to induce cachexia *in vivo* led to an extensive evaluation of its role in energy homeostasis [3]. TNF-α alters gene expression of metabolically important tissues such as adipose tissue and liver [63] and impairs the insulin signaling by activation of serine kinases that increase the insulin receptor substrate-1 and -2 phosphorylation, increasing its

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 nuclear factor kappaB [65].

Obesity and Weight Loss: The Influence of Thyroid Hormone on Adipokines 221

inhibition of plasmin production, contributing to vascular architecture remodeling and

*Adipsin and acylation stimulating protein* (ASP) – Also secreted by adipose tissue it has an important effect on lipogenesis [59]. APS inhibits the lipolysis by inhibition of hormone sensitive lipase (HSL), and stimulating lipogenesis by increasing GLUT4 translocation from cytosol to membrane; increases glycerol-3-phosphate production and increases diacylglycerol acyltransferase activity, an catalyst enzyme in triglycerides synthesis [74].

*Proteins of the renin angiotensin system* (RAS) – Pathogenic models have been proposed to explain the association between adiposity and the renin angiotensin system [75]. This seems to be related to fat accumulation in adipose tissue, as well as its involvement in inflammatory and atherogenic process. Adipose tissue secretes many proteins related to the RAS as renin, angiotensinogen (AGT), angiotensin I, angiotensin II, angiotensin type I receptors (AT1) and type 2 (AT2) angiotensin-converting enzyme (ACE), and other proteases capable of producing angiotensin II (chymase, cathepsins D and G) [76, 77]. The angiotensin I receptor is secretion inductor of series 2 prostaglandins which participates in preadipocytes cell differentiation, and the angiotensin II stimulates adipocytes differentiation and lipogenesis in time of angiotensin I to II conversion, indicating their

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

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

atherosclerotic process [66, 73].

Thus affects both the glucose and the lipid metabolism.

involvement in the accumulation of fat mass process [78].

**3. Adipokines and thyroid hormones** 

its presence [81].

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

*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 inhibition of plasmin production, contributing to vascular architecture remodeling and atherosclerotic process [66, 73].

*Adipsin and acylation stimulating protein* (ASP) – Also secreted by adipose tissue it has an important effect on lipogenesis [59]. APS inhibits the lipolysis by inhibition of hormone sensitive lipase (HSL), and stimulating lipogenesis by increasing GLUT4 translocation from cytosol to membrane; increases glycerol-3-phosphate production and increases diacylglycerol acyltransferase activity, an catalyst enzyme in triglycerides synthesis [74]. Thus affects both the glucose and the lipid metabolism.

*Proteins of the renin angiotensin system* (RAS) – Pathogenic models have been proposed to explain the association between adiposity and the renin angiotensin system [75]. This seems to be related to fat accumulation in adipose tissue, as well as its involvement in inflammatory and atherogenic process. Adipose tissue secretes many proteins related to the RAS as renin, angiotensinogen (AGT), angiotensin I, angiotensin II, angiotensin type I receptors (AT1) and type 2 (AT2) angiotensin-converting enzyme (ACE), and other proteases capable of producing angiotensin II (chymase, cathepsins D and G) [76, 77]. The angiotensin I receptor is secretion inductor of series 2 prostaglandins which participates in preadipocytes cell differentiation, and the angiotensin II stimulates adipocytes differentiation and lipogenesis in time of angiotensin I to II conversion, indicating their involvement in the accumulation of fat mass process [78].
