**2.2. Resistin**

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

Obesity and Weight Loss: The Influence of Thyroid Hormone on Adipokines 219

Were identified two adiponectin receptors isoforms (Adipo-R1 and -R2) [57]. This receptors present seven transmembrane domains but are functionally different of receptors coupled to G protein. AdipoR1 is expressed mainly in muscle tissue and has high affinity for globular adiponectin, and low affinity for full-length adiponectin. AdipoR2 has high expression in liver and has intermediate affinity for both isoforms of circulating adiponectin. Thus, it is noted that the biological effects of adiponectin depends not only on circulating levels or the properties of each isoform but also receptor subtype and its expression in each tissue [3].

Adiponectin anti-inflammatory and anti-atherogenic actions occurs through decreased expression of adhesion molecule-1 (via reduced expression of TNF-alpha activity and resistin); decreased macrophage chemotaxis to fat cells formation; and inhibition of inflammatory signaling in endothelial tissue [58]. It increases insulin sensitivity via increased fatty acid oxidation and glucose uptake and utilization in skeletal muscle and adipose tissue; reduction of hepatic glucose release, leading to better control of glucose serum levels, free fatty acids and triglycerides [59]. In rat adipocytes, *in vitro*, the 60% reduction in adiponectin expression increased significantly insulin resistance. The presence of nucleotide polymorphisms in adiponectin caused by genetic or environmental factors (diet rich in fat, for example), can be a determining factor in reducing their insulin

In the liver, adiponectin increases insulin sensitivity by reducing nonesterified fatty acids uptake, increasing fatty acid oxidation and decreasing glucose output. In muscle, adiponectin stimulates glucose metabolism and fatty acid oxidation. In the endothelium, it inhibits monocyte adherence by reducing adhesion molecules; inhibits macrophages transformation and reduces migrating smooth muscle cells proliferation in response to growth factors. Adiponectin also increases nitric oxide production by endothelial cells and stimulates angiogenesis. Taken together, these effects suggest that adiponectin is the only adipokine that present antidiabetic, anti-inflammatory and anti-atherogenic effects [3].

*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

sensitizing action [60].

**2.4. Others adipokines** 

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 glucose uptake [46].

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

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 be determined [3].
