Csilla Terézia Nagy1, Gábor Koncsos1, Zoltán V Varga1, Tamás Baranyai1, Sebestyén Tuza1, Ferenc Kassai2,3, Aliz Judit Ernyey2,3, István Gyertyán2,3, Kornél Király1, Attila Oláh4, Tamás Radovits4, Béla Merkely4, Nóra Bukosza5, Gábor Szénási5, Péter Hamar5,6,7, Domokos Mathé8, Krisztián Szigeti8, Csilla Pelyhe1, Marek Jelemenský9, Zsófia Onódi1, Zsuzsanna Helyes10, Rainer Schulz11, Zoltán Giricz1,12, Péter Ferdinandy1,12. 1. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary. 2. MTA-SE NAP B Cognitive Translational Behavioural Pharmacology Group, Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary. 3. Institute of Cognitive Neuroscience and Psychology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary. 4. Heart and Vascular Center, Semmelweis University, Budapest, Hungary. 5. Institute of Pathophysiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary. 6. Clinical Experimental Research Institute, Faculty of Medicine, Semmelweis University, Budapest, Hungary. 7. Translational Medicine Institute, Faculty of Medicine, Pécs University, Pécs, Hungary. 8. Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary. 9. Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia. 10. Department of Pharmacology and Pharmacotherapy, Medical School and Szentágothai Research Centre, University of Pécs, Pécs, Hungary. 11. Institute of Physiology, Justus-Liebig University Giessen, Germany. 12. Pharmahungary Group, Szeged, Hungary.
Abstract
BACKGROUND AND PURPOSE: Incidence and severity of obesity are increasing worldwide, however, efficient and safe pharmacological treatments are not yet available. Certain MAO inhibitors reduce body weight, although their effects on metabolic parameters have not been investigated. Here, we have assessed effects of a widely used, selective MAO-B inhibitor, selegiline, on metabolic parameters in a rat model of diet-induced obesity. EXPERIMENTAL APPROACH: Male Long-Evans rats were given control (CON) or a high-fat (20%), high-sucrose (15%) diet (HFS) for 25 weeks. From week 16, animals were injected s.c. with 0.25 mg·kg-1 selegiline (CON + S and HFS + S) or vehicle (CON, HFS) once daily. Whole body, subcutaneous and visceral fat was measured by CT, and glucose and insulin tolerance were tested. Expression of glucose transporters and chemokines was assessed by quantitative RT-PCR. KEY RESULTS: Selegiline decreased whole body fat, subcutaneous- and visceral adiposity, measured by CT and epididymal fat weight in the HFS group, compared with HFS placebo animals, without influencing body weight. Oral glucose tolerance and insulin tolerance tests showed impaired glucose homeostasis in HFS and HFS + S groups, although insulin levels in plasma and pancreas were unchanged. HFS induced expression of Srebp-1c, Glut1 and Ccl3 in adipose tissue, which were alleviated by selegiline. CONCLUSIONS AND IMPLICATIONS: Selegiline reduced adiposity, changes in adipose tissue energy metabolism and adipose inflammation induced by HFS diet without affecting the increased body weight, impairment of glucose homeostasis, or behaviour. These results suggest that selegiline could mitigate harmful effects of visceral adiposity.
BACKGROUND AND PURPOSE: Incidence and severity of obesity are increasing worldwide, however, efficient and safe pharmacological treatments are not yet available. Certain MAO inhibitors reduce body weight, although their effects on metabolic parameters have not been investigated. Here, we have assessed effects of a widely used, selective MAO-B inhibitor, selegiline, on metabolic parameters in a rat model of diet-induced obesity. EXPERIMENTAL APPROACH: Male Long-Evans rats were given control (CON) or a high-fat (20%), high-sucrose (15%) diet (HFS) for 25 weeks. From week 16, animals were injected s.c. with 0.25 mg·kg-1 selegiline (CON + S and HFS + S) or vehicle (CON, HFS) once daily. Whole body, subcutaneous and visceral fat was measured by CT, and glucose and insulin tolerance were tested. Expression of glucose transporters and chemokines was assessed by quantitative RT-PCR. KEY RESULTS:Selegiline decreased whole body fat, subcutaneous- and visceral adiposity, measured by CT and epididymal fat weight in the HFS group, compared with HFS placebo animals, without influencing body weight. Oral glucose tolerance and insulin tolerance tests showed impaired glucose homeostasis in HFS and HFS + S groups, although insulin levels in plasma and pancreas were unchanged. HFS induced expression of Srebp-1c, Glut1 and Ccl3 in adipose tissue, which were alleviated by selegiline. CONCLUSIONS AND IMPLICATIONS: Selegiline reduced adiposity, changes in adipose tissue energy metabolism and adipose inflammation induced by HFS diet without affecting the increased body weight, impairment of glucose homeostasis, or behaviour. These results suggest that selegiline could mitigate harmful effects of visceral adiposity.
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