**5.4. Others adipokines**

*TNF-α* - The first information about the TNF-α biological effects indicated an involvement in insulin resistance, weight loss and anorexia. The increase in lipolysis result from TNF-α stimulus in hormone-sensitive lipase expression, leading to decreased activity of lipoprotein lipase. However, more recent investigations have revealed a molecular mechanism of weight loss on TNF-α levels, showing TNF-α expression is increased in obesity and decreases with weight loss, thereby improving insulin sensitivity [135, 198]. After weight loss there is a decrease of macrophages number in adipose tissue [199], this can lead to decreased TNF-α levels, since both adipose tissue and macrophages produce this cytokine. There are few studies correlating the thyroid status with TNF-α levels in weight loss. Patients with HIV tend to lose weight and in some cases it is observed a decrease in T3 levels accompanied by increased TNF-α levels, when these individuals are compared to patients with HIV with normal T3 levels. These results corroborate to other study linking the sick euthyroid syndrome to high TNF-α levels in cachectic patients with HIV [200].

Obesity and Weight Loss: The Influence of Thyroid Hormone on Adipokines 231

body mass index and variations in PAI-1 levels. Moreover, the largest decrease in PAI-1 levels was observed in the obese children with the highest previous PAI-1 levels [209]. Weight loss induced by a low calorie diet causes a decrease in plasma PAI-1 levels especially among obese individuals [210, 211], and these increase once again if weight is regained [212]. Surgically removing fat confers the same beneficial effect [212]. Antidiabetic drugs such as thiazolidinediones, metformin, and AT1-receptor antagonists reduce adipose PAI-1 expression [211]. Interestingly, waist-to-hip ratio, a reflection of central fat accumulation, has been found in women to be the only independent predictor of circulating PAI-1 activity [213]. In individuals subjected to a calorie restricted diet, PAI-1 levels were more closely related to changes in the central fat deposit than in the subcutaneous fat deposit [214]. Thus, the visceral fat deposit may be importante for the occurrence of increased plasma PAI-1 levels. There is few data available regarding the thyroid hormones and PAI-1. Studies have been focused on serum measurements, in severe hypothyroidism was found decreased PAI-1 levels [215], while in hyperthyroidism some studies show increased [113, 216, 217], other

*RAS* - Studies with RAS manipulation (deletion) showed that function loss in any single component of RAS tested so far, provides protection from diet-induced obesity and insulin resistance [221-224]. Therefore, RAS seems to play a role in obesity development; however systemic RAS overactivation via gene overexpression or chronic Ang II infusion also induces insulin resistance, but not necessarily obesity [225]. Weight loss in humans results in decreases in circulating components of the RAS [226]. In fact, Engeli et al. [226] suggest that a 5% reduction in body fat mass can reduce meaningfully the RAS in plasma and adipose tissue, which may contribute to reduce blood pressure. Genetic polymorphisms of RAS may also play a role in response to weight loss in obese individuals [227]. Decrease of RAS leads to improvement in insulin sensitivity, blood pressure, and renal function. As RAS interacts with others adipokines, reduction in RAS concentrations followed weight loss may also contributes to improvement of other adipokines levels and, consequently, improve other metabolic disorders [226, 228]. As mentioned, thyroid hormones appear to stimulate expression and synthesis of RAS components [175-177]. However, precise interaction between thyroid

hormones and RAS components in weight loss process are scarce in the literature.

so far. Future research studying these associations is awaited.

**6. The use of TRβ analogues** 

Literature on newer adipokines and thyroid disorders is scarce. No data on ASP and weight loss is available and no data on these adipokines and thyroid hormone have been published

Thyroid hormone analogues, termed thyromimetics, are molecules with activate signaling pathway property similar to thyroid hormones, sometimes with tissue specificity or by activating a singular pathway stimulated by thyroid hormones, other with less effect, but even with a way close to thyroid hormones. The thyromimetics have a great pharmaceutical potential since they present certain specificity as intracellular signaling that stimulate and thus may have a tissue specific action. However, only the past 20 years, with increasing

decreased [83, 218] as well as unaffected PAI-1 levels [219, 220].

**Figure 4.** Thyroid hormone may modulate adipokines concentration by regulating adipose tissue metabolism by, *i.e.*, increasing lipid oxidation leading to body fat decreased. The exact influence of thyroid hormone on adipokines remains unclear.

*IL-6* - IL-6 levels decrease with weight loss [140-142]. The intracerebroventricular administration of this cytokine can decrease body fat [201]. Association studies between thyroid hormones and IL-6 in weight loss are scarce, but studies in critically patients demonstrated a direct association between decreased T3 levels and high IL-6 plasma levels, demonstrating that approximately 28% of T3 fall could be directly related to increased IL-6 [202]. In another study, of 270 patients admitted to intensive care unit, serum T3, T4 and IL-6 were measured and again was observed a negative correlation between T3 and T4 levels and IL-6 levels, demonstrating that this cytokine could be an important factor associated with decreased circulating thyroid hormones levels [203].

*MCP-1* - Chronic inflammation associated with obesity exists in dogs, and it is evident that weight loss decreases this inflammation as observed by decreasing MCP-1 after weight loss [204]. In agreement, Kanda et al. [205] demonstrated that MCP-1 deficient mice have reduced adipose tissue macrophage infiltration. Few studies correlate weight loss and MCP-1 levels, and no data was found regarding weight loss, MCP-1 and thyroid association.

*PAI-1* - Weight loss secondary to calorie restriction is associated with reduced PAI-1 activity in adults [206, 207]. However, in children no significant change in PAI-1 levels was observed in 43 obese children after a physical training program [208]. This may be explain by the increase in fibrinolytic activity due to a decrease in PAI-1 antigen levels in obese children after weight loss, and a significant positive correlation was observed between variations in body mass index and variations in PAI-1 levels. Moreover, the largest decrease in PAI-1 levels was observed in the obese children with the highest previous PAI-1 levels [209]. Weight loss induced by a low calorie diet causes a decrease in plasma PAI-1 levels especially among obese individuals [210, 211], and these increase once again if weight is regained [212]. Surgically removing fat confers the same beneficial effect [212]. Antidiabetic drugs such as thiazolidinediones, metformin, and AT1-receptor antagonists reduce adipose PAI-1 expression [211]. Interestingly, waist-to-hip ratio, a reflection of central fat accumulation, has been found in women to be the only independent predictor of circulating PAI-1 activity [213]. In individuals subjected to a calorie restricted diet, PAI-1 levels were more closely related to changes in the central fat deposit than in the subcutaneous fat deposit [214]. Thus, the visceral fat deposit may be importante for the occurrence of increased plasma PAI-1 levels. There is few data available regarding the thyroid hormones and PAI-1. Studies have been focused on serum measurements, in severe hypothyroidism was found decreased PAI-1 levels [215], while in hyperthyroidism some studies show increased [113, 216, 217], other decreased [83, 218] as well as unaffected PAI-1 levels [219, 220].

*RAS* - Studies with RAS manipulation (deletion) showed that function loss in any single component of RAS tested so far, provides protection from diet-induced obesity and insulin resistance [221-224]. Therefore, RAS seems to play a role in obesity development; however systemic RAS overactivation via gene overexpression or chronic Ang II infusion also induces insulin resistance, but not necessarily obesity [225]. Weight loss in humans results in decreases in circulating components of the RAS [226]. In fact, Engeli et al. [226] suggest that a 5% reduction in body fat mass can reduce meaningfully the RAS in plasma and adipose tissue, which may contribute to reduce blood pressure. Genetic polymorphisms of RAS may also play a role in response to weight loss in obese individuals [227]. Decrease of RAS leads to improvement in insulin sensitivity, blood pressure, and renal function. As RAS interacts with others adipokines, reduction in RAS concentrations followed weight loss may also contributes to improvement of other adipokines levels and, consequently, improve other metabolic disorders [226, 228]. As mentioned, thyroid hormones appear to stimulate expression and synthesis of RAS components [175-177]. However, precise interaction between thyroid hormones and RAS components in weight loss process are scarce in the literature.

Literature on newer adipokines and thyroid disorders is scarce. No data on ASP and weight loss is available and no data on these adipokines and thyroid hormone have been published so far. Future research studying these associations is awaited.
