Leptin Regulation of the Thyroids: Negative Regulation on Thyroid Hormone Levels in Euthyroid Subjects and Inhibitory Effects on Iodide Uptake and Na+/I- Symporter mRNA Expression in Rat FRTL-5 Cells

Abstract

Abstract. Leptin receptors are distributed throughout the body and leptin has been shown to have various effects. As we have recently demonstrated a positive correlation between serum leptin levels and TSH in euthyroid subjects, we investigated the effect of leptin on the thyroids. It was observed that serum leptin levels were negatively correlated with free thyroxine/TSH ratios in the serum of euthyroid female subjects. This suggests that leptin may modulate TSH effects. RT-PCR for leptin receptor expression revealed that FRTL-5 cells possess the gene transcript to the long cytoplasmic form of the receptor. Leptin actually appeared to induce an increase in c-fos mRNA expression. However, it inhibited iodide uptake typically induced by both TSH and dibutyryl cAMP, while leptin did not inhibit TSH-induced cAMP production or TSH-stimulated DNA synthesis in 4H medium (in the absence of insulin and TSH). Leptin also was observed to inhibit TSH-and dibutyryl cAMP-induced Na + /I -symporter and thyroglobulin mRNA expression. Lastly, leptin was seen to inhibit TSH-stimulated thymidine incorporation in 5H medium. Taken together, these results suggest that leptin suppresses TSH-induced thyroid function. Therefore, we hypothesized that leptin may be one of the regulators of thyroid function in obese patients. LEPTIN, the gene product of the ob gene, is produced by fat tissues and acts in an endocrine fashion by reporting the size of the adipose tissue mass to hypothalamic leptin receptors that ultimately control the appetite and energy expenditure [1]. Recent studies show that leptin receptors are widely distributed throughout the body and that they have a variety of effects on a number of tissues. For example, functional leptin receptors are expressed in the ovary where leptin mediates the signal between fat storage and the reproductive system [2]. As for the thyroid, we earlier demonstrated a positive relation between serum leptin and TSH levels in euthyroid subjects [3]. In addition to our data, Wesche et al. reported that in obese subjects a larger thyroid size was associated with slightly but significantly higher TSH and lower free thyroxine (fT 4 ) serum levels [4]. As serum leptin concentrations positively correlate with body fat mass or body mass index, serum leptin levels should be higher in the obese subjects. We therefore assumed that leptin stimulates proliferation of thyroid cells or inhibits thyroid hormone synthesis stimulated by TSH in obese subjects by some mechanism. In order to clarify the possible role of leptin in regulation of thyroid function, we first analyzed the relation between serum leptin concentrations and fT 4 /TSH ratio in order to re-confirm the clinical relationship between obesity and thyroid function in euthyroid subjects. Next we investigated the direct actions of leptin on

Tissue-specific deiodinase regulation during food restriction and low replacement dose of leptin in rats

“…These observations indicate a direct stimulatory effect of leptin on the thyroid gland or on the peripheral metabolism of T 4 and T 3 in humans with reduced body weight. On the other hand, recent studies have shown direct inhibitory effects of leptin on the ability of thyrocytes to take up iodide in rat thyroid cells (27,37).The transport of iodide is a fundamental step in thyroid hormone biosynthesis and is catalyzed by the Na ϩ -I Ϫ symporter (NIS), an intrinsic membrane protein localized at the basolateral membrane of thyrocytes (20). Leptin directly inhibits iodide uptake induced by TSH in FRTL-5 cells (27) and in thyroids from fed adult rats (37).…”

“…These observations indicate a direct stimulatory effect of leptin on the thyroid gland or on the peripheral metabolism of T 4 and T 3 in humans with reduced body weight. On the other hand, recent studies have shown direct inhibitory effects of leptin on the ability of thyrocytes to take up iodide in rat thyroid cells (27,37).…”

“…Leptin directly inhibits iodide uptake induced by TSH in FRTL-5 cells (27) and in thyroids from fed adult rats (37). Thyroperoxidase (TPO) is a key enzyme in thyroid hormone biosynthesis that catalyzes iodide oxidation, organification, and the coupling of iodothyrosines to produce T 3 and T 4 (39,44).…”

Differential roles of leptin in regulating cell migration in thyroid cancer cells

“…In rat thyroid FRTL-5 cells, leptin induced an increase in c-fos expression and TSHstimulated cAMP production (15). However, leptin inhibited iodide uptake induced by TSH as well as TSH-and cAMPinduced NIS and thyroglobulin expression.…”

“…Leptin stimulates thyrotropin-releasing hormone (TRH) expression in the hypothalamus, and subsequently production of thyroid-stimulating hormone (TSH). Peripherally, limited studies suggest that leptin has direct actions on the thyroid gland (15). It has been demonstrated that rats receiving prolonged leptin treatment had increased thyroid gland weight (16).…”