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Thermogenic and molecular response to beta-3 adrenergic receptor agonist treatment in rats with constitutionally altered serotonin homeostasis

The key component of the obesity is a long-term dysregulation of energy balance, i.e. energy consumption and expenditure. In view of lack of appetite suppressant drugs, approaches to increase energy expenditure, including by increasing thermogenesis, are suggested as a new anti-obesity treatments. Brown adipose tissue (BAT) is an organ with a large ability to convert chemical energy into heat. BAT activity is directly regulated by adrenergic stimulation which triggers an acute thermogenic response and induces expression of key genes that serve to increase the thermogenic BAT capacity. A biogenic monoamine serotonin (5HT) was recently shown to affect adaptive thermogenesis in BAT. To better understand the role of endogenous 5HT signalling in BAT functioning, we use Wistar- Zagreb 5HT (WZ-5HT) rats, animal model consisting of two sublines of rats with constitutionally altered 5HT homeostasis (high- 5HT and low-5HT subline). Previously we have shown differences in response of WZ-5HT sublines to stimulation of BAT activity by endogenous noradrenaline produced by cold adaptation. Here we investigated the physiological and molecular effects of pharmacological stimulation of BAT activity with highly selective β3-adrenergic receptor agonist. Animals from two 5HT sublines were treated for 6 days with CL-316, 243 (1mg /kg/day, i.p.) and their body weight and food intake were monitored. At the end of experiment we measured temperature above the interscapular BAT (by infrared thermography), determined BAT mass and evaluated BAT protein (by ELISA) and mRNA (by RT-qPCR) levels of key protein involved in dissipating energy into heat (uncoupled protein- 1, UCP-1). mRNA levels of several transcription factors involved in brown adipogenesis were also measured. Results show that rats from the low-5HT subline (i.e. hyposerotonergic animals) as compared to rats from the high-5HT subline have increased BAT activation in response to CL treatment, as evidenced by higher body weight loss, decrease in food intake and increase in skin temperature above BAT. These functional differences between the sublines were accompanied by different expression patterns of BAT specific genes (UCP1, Dio2) and related transcription factors (Ppara, Cebpb, Pparg1a). We conclude that individual differences in serotonergic tone affect the response of BAT to pharmacologic activation by thermogenic β3- adrenergic agonist.

serotonin ; brown adipose tissue ; beta-3-adrenergic receptor agonist

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