Running title: LEPTIN AND THE THYROID GLAND Academy Section: BIOMEDICAL SCIENCES

Leptin plays a major role in the regulation of energy intake and energy expenditure, triggering effects on several tissues, such as the hypothalamic-pituitarythyroid axis. The reported effects of leptin on the thyroid are controversial, being mainly explored during energy imbalance. Therefore, the aim of this study was to evaluate the effects of leptin on thyroid function of rats fed ad libitum distinguishing direct leptin responses from those mediated by leptin-dependent suppression of food intake by comparing leptin-treated (L) with pair-fed (PF) animals. Leptin administration resulted in a decrease of 10% in food intake. Reduced mass gain was observed on both L and PF groups. Leptin administration decreased serum corticosterone, which did not occur in the PF group. TSH levels were reduced in PF group, but not in the L group. Both L and PF animals presented reduced iodide uptake and type 1 deiodinase (D1) activity in the thyroid gland. A decrease of D1 activity was also found in the PCCl3 rat thyroid cell lineage treated with leptin. Taken together the data suggest that leptin exerts paradoxical effects: a stimulatory effect on the hypothalamic-pituitary-thyroid axis by increasing TSH levels while directly inhibiting thyrocyte function in a TSH-independent fashion.