Effects of Diet-Induced and Melanocortin Obesity on the Expression of Tryptophan Hydroxylase 2 in Midbrain and Hypothalamus Neurons in Mice

The serotonin system of the brain plays key roles in regulating behavior and cognitive functions, as well as in energy metabolism. This involves serotoninergic neurons in the midbrain expressing the enzyme tryptophan hydroxylase type 2 (TPH-2), which catalyzes the synthesis of serotonin, and hypothalamic neurons expressing serotonin receptors. Changes in the expression and distribution of TPH-2 in midbrain neurons on obesity remain poorly studied. In addition, it has been suggested that serotonin may also be synthesized in hypothalamic neurons influencing the serotonin system of the hypothalamus, though no data on the expression and possible localization of TPH-2 in hypothalamic neurons have been obtained. The aim of the present work was to study TPH-2 expression in the midbrain and its distribution in neurons in the arcuate, paraventricular, and supraoptic nuclei of the hypothalamus in mice with diet-induced obesity (DIO) and in agouti mice with genetically determined melanocortin-type obesity. Expression of the TPH-2 gene in the hypothalamus of C57Bl/6J mice was demonstrated and double immunolabeling studies provided the first evidence that this enzyme is located in proopiomelanocortin (POMC)-immunopositive neurons in the arcuate nuclei and vasopressin-immunopositive neurons in the paraventricular and supraoptic nuclei. In both types of obesity, TPH-2-immunopositive granules in POMC- and vasopressin-immunopositive neurons increased, though expression of the Tph2 gene increased only in agouti mice. TPH-2 content in the midbrain of DIO mice decreased, while there was no change in agouti mice. These results provide evidence of the important role of serotonin synthesized in the hypothalamic which, along with serotonin arriving from the midbrain, is involved in compensatory changes in hypothalamus signaling in obesity. Detection of TPH-2-immunopositive hypothalamic neurons of different ergicities and able to synthesize serotonin points to the existence of novel mechanisms of autocrine and paracrine serotonin regulation in the hypothalamus, including in obesity.