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, in particular
susceptibility to diet-induced obesity and capability for cold-induced thermogenesis. Results of
the proposed project will substantially advance the field of neuroadipology regarding the role
of serotonin system in maintaining of energy homeostasis. Greater understanding of
integrative mechanisms and pathogenesis is essential in order to develop more effective
therapies for combat obesity. The project also have potential to establish a novel rodent model
for study obesity that would be complementary to existing models generated by genetic
engineering or obzained by diet-induced approaches.