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Effect of high-fat diet on glucose and lipid metabolism in rats with constitutionally altered serotonin homeostasis

Obesity is reaching epidemic proportions worldwide. It occurs as consequence of unbalanced food intake and energy consumption. Serotonin (5HT) is a biogenic monoamine with important roles in maintaining energy homeostasis. While brain 5HT system suppresses feeding, peripheral 5HT regulates glucose and lipid metabolism promoting obesity. Recently, compounds targeting peripheral 5HT system have been suggested as a potential anti-obesity drug. The Wistar-Zagreb 5HT (WZ-5HT) rat model was developed by selective breeding towards extremes of platelet 5HT level. Its high-5HT subline is characterised with hyperserotonemia, lifelong elevated body weight and adiposity, as compared to the low-5HT subline. To better understand the role of constitutionally altered peripheral 5HT homeostasis in developing obesity, we fed animals from both WZ-5HT sublines with high-fat diet (HFD, 45% kcal from fat, 11 weeks) and examined HFD-induced changes in blood glucose homeostasis. In addition, we investigated changes in white adipose tissue (WAT) expression of genes involved in glucose and lipid metabolisam and assesed blood levels of the respective proteins, using RT-qPCR and ELISA, respectively. Blood plasma levels of glucose as well as of insulin and glucagon, two main hormones regulating glucose homeostasis in a opposite manner, were affected by HFD only in animals from low-5HT, but no high-5HT, subline. This was further confirmed by calculating Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) score, which was significantly elevated by HFD only in low-5HT animals. On the other hand, HFD altered WAT expression of insulin receptor (Insr) and glucose transporter member 1 (Glut1) only in high-5HT subline, while glucose transporter member 4 (Glut4) was downregulated by HFD similarly in both sublines. As to lipid metabolism, HFD increased WAT expression of adipose trygliceride lipase (Atgl) and fatty acid-binding protein 4 (Fabp4), and decreased WAT expression of fatty acid synthesis (Fasn) similarily in both sublines, while significant reduction in plasma level of Fasn was present only in high-5HT subline. Altogether, results demonstrate that constitutional differences in peripheral serotonin system activity affect biochemical and molecular response of animals to HFD.

serotonin ; obesity ; lipid ; glucose

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