**4.1. Leptin**

A potential interaction between leptin and thyroid hormones has been suggested since both hormones are associated with body weight and energy expenditure regulation.

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 controversial (Figure 3).

**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: triiodothyronine.

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 physiological and supraphysiological doses.

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

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 relationship between leptin and thyroid hormones.
