The rise in obesity has driven a major interest in the mechanisms maintaining energy homeostasis, a complex physiological process which includes interactions of various central and peripheral regulatory molecules. It is known that serotonin (5HT) - mediated mechanisms play a role in the pathophysiology of obesity, but results from recent studies utilizing genetic perturbations of the serotonin system are often at odds with the historical notion that increased 5HT bioavailability leads to body weight reduction, and highlight the need to better understand integrative mechanisms at work during lifelong alterations in 5HT signaling. This project is aimed to study the impact of constitutionally altered activity of 5HT system on the regulation of hypothalamic-adipose tissue axis that regulates energy balance. For this purpose we plan to use an original animal model, Wistar-Zagreb 5HT rats, developed in our laboratory by the use of selective breding toward extreme activities of peripheral 5HT transporter, a key regulator of 5HT bioavailability. As a result of genetic selection two sublines of the model, high-5HT and low-5HT subline, show constitutional differences in central and peripheral 5HT homeostasis. One of the consequences of genetic selection is also a markedly overweight phenotype of high-5HT animals. We will investigate biological basis of interplay between increased 5HT tone and adiposity in the hyperserotonergic subline, and their functional consequences. Studies at the molecular level will be focused on the expression of adipocyte- and hypothalamic-derived peptides, their receptors and downstream signaling as well as transcriptional factors and cofactors involved in the regulation of adipogenesis and energy homeostasis in general. Studies on the whole body level will include investigations of the functional responses of 5HT sublines to specific physiological challenges - susceptibility to diet-induced obesity and capability for cold-induced thermogenesis.