High-Fat Diet Increases Thyrotropin and Oxygen Consumption without Altering Circulating 3,5,3′-Triiodothyronine (T3) and Thyroxine in Rats: The Role of Iodothyronine Deiodinases, Reverse T3 Production, and Whole-Body Fat Oxidation

This study investigated the effects of obesity induced by high-fat (HF) diet on thyroid function and whole-body energy balance. To accomplish that, we assessed the effects of 8 wk of HF diet on several parameters of hypothalamus-pituitary-thyroid axis function. Serum total T4 and T3, rT3, and TSH, the activity of type 1 and type 2 deiodinases in central and peripheral tissues were determined. Also, we measured in vivo energy balance, substrate partitioning, and markers of leptin resistance. Here we provide novel evidence that prolonged positive energy balance acquired by feeding a HF diet induced hyperactivation of the hypothalamus-pituitary-thyroid axis, which was characterized by 2.24-, 1.6-, and 3.7-fold elevations in hypothalamic TRH expression, thyroid iodide uptake, and serum TSH, respectively. Serum T4 and T3 were normal together with augmented deiodinase type 1 activity in liver (1.3-fold) and kidney (1.2-fold) and increased (1.5-fold) serum rT3 in HF rats. Despite no increase in circulating levels of T3 and T4, whole-body oxygen consumption was increased, and substrate metabolism was shifted toward fat oxidation in HF rats. These in vivo metabolic adjustments were mainly driven by the fat content of the diet. Furthermore, spontaneous dark cycle physical activity was reduced by 30% in rats fed a HF diet, which limited energy expenditure and favored the development of obesity. Our findings provide new insight into the endocrine and physiological mechanisms that underlie the alterations in thyroid hormone availability, energy balance, and metabolic partitioning in HF diet-induced obesity. High-fat diet causes hyperactivation of the hypothalamus-pituitary-thyroid axis; however, alteration in the activity of deiodinases and reduced spontaneous physical activity limit energy expenditure and favor the development of obesity.