The Effect of Diet-Induced and Melanocortin Obesity on Expression of Tryptophan Hydroxylase 2 in the Dorsal Raphe Nucleus and Ventral Tegmental Area in Mice

Abstract

Serotonin and its signaling pathways are involved in the central regulation of feeding behavior and energy metabolism. The most important role in this regulation is played by dopaminergic neurons of the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA) which express tryptophan hydroxylase 2 (TPH2) catalyzing the rate-limiting step in serotonin synthesis. Changes in activity of the serotonin-synthesizing system in the DRN and VTA may significantly contribute to the development of metabolic disorders, including obesity. However, data on TPH2 expression in these brain regions in obesity are unavailable. The aim of this work was to compare immunohistochemically TPH2 expression in the DRN and VTA of C57Bl/6J (a/a) female mice with a diet-induced obesity (DIO) (caused by 8- and 16-week intake of high-calorie food) and C57Bl/6J (Ay/a) agouti mice with genetically predetermined melanocortin obesity. Double immunolabeling demonstrated that in DIO mice with a 16-week high-calorie diet TPH2 expression in the DRN (the main cerebral source of serotonin) decreases while in the VTA increases. In agouti mice, TPH2 expression in the DRN did not change while in the VTA increased. In DIO mice with a 8-week high-calorie diet and in C57Bl/6J (a/a) mice resistant to this diet, TPH2 expression did not change both in the DRN and VTA. Thus, DIO mice kept on a long-term (16 weeks) diet and agouti mice with melanocortin obesity exhibit specific changes in the serotonin synthesis that are lacking in diet-resistant mice. This finding indicates a crucial role of serotonin signaling in the organismal response to excessive caloric intake.