Research
Research
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At the very beginning, our team performed the studies of the involvement of the glucocorticoid hormones in the pathophysiology of the metabolic syndrome and related diseases. A worldwide epidemic of metabolic syndrome and its comorbidities has emerged in the last couple of decades and it is now considered to be one of the leading medical problems of modern societies. Metabolic syndrome is presented by an assembly of interwoven disorders which predispose the development of type 2 diabetes and cardiovascular diseases, and basically include: obesity, hyperglycemia and insulin resistance, dyslipidemia and hypertension. In the first few years, we focused on the molecular mechanisms linking glucocorticoids to lipogenesis, lipolysis and low-grade inflammation as well as the corresponding insulin pathways in the metabolically active tissues. We also studied the glucocorticoid-dependent regulation of the neuroendocrine control of food intake, together with the changes in neural plasticity. In all these studies we used both male and female Wistar rats kept on a fructose enriched (10% or 60% solution in tap water) diet for nine weeks immediately post-weaning, thus reflecting the modern, energetically unbalanced nutrition, typically spiked with fructose (corn) syrup as a lipogenic disruptor of satiety and energy storage signals. For further corresponding analyses in the specific context of the attenuated glucocorticoid-controlled inflammation, we used a genetically modified (MIF deficient) mouse model treated with a 20% fructose enriched diet.
An additional line of research has begun during this first period, and focused on the glucocorticoid influence in the polycystic ovarian syndrome (PCOS), an endocrine and reproductive disease with a testosterone surplus as the principal characteristic. Most cases of PCOS present with prominent and pathophysiologicaly relevant metabolic aspects, most importantly insulin resistance and/or obesity. We gained a rat model of this disease by a 9-week long delivery of the active form of testosterone (5α - dihydrotestosterone (DHT)) to rats immediately post weaning, and analyzed the metabolic parameters and molecular pathways similar to the ones studied post fructose treatment. At the moment, we are working on upgraded rat model, including 9-week long delivery of DHT and obesity induced by litter size manipulations, to understand the contribution of increased caloric intake during early postnatal period to the adverse metabolic outcomes and to try to clarify what is the fundamental disorder in this disease - androgen surplus or insulin resistance.
In 2014, in cooperation with Professor Luc Tappy and his associates from the University of Lausanne, Switzerland, we started a new project, of which the main research focus was the role of glucocorticoids in the metabolic disturbances consequent to the combined effects of fructose rich diet and chronic unpredictable stress, as the most influential glucocorticoid-linked environmental chalenges of modern societes. In this study, we used a new rat model with 9 week-long fructose (20% solution in tap water) diet combined with a three week long chronic unpredictable stress regime at the very end of treatment.
After researching the key molecular aspects of lipid and glucose metabolism in all of the aforementioned animal models of metabolic disturbances, we realized it was time to broaden our horizons, not only from the standpoint of the main research theme, but methodologically as well. We thus decided to shift our focus on the role of gut microbiota in obesity, specifically on the mechanistic aspects of microbial influence on weight loss/gain. With this in mind, we recently launched a completely new cooperation with “Čigota”, a medical center located at Zlatibor Mt, Serbia, specializing in obesity treatment through strictly planned dietary and workout regimes, implemented under careful medical supervision. This program, called “Čigotica”, has been established in 2008, as part of the national quest to fight the rising childhood and adolescent obesity epidemic in Serbia, and currently enrolls large groups of adolescents of both sexes. Our team has been allowed access to the specimens of patient feces and their basic morphological and biochemical data, at the start and post completion of the three-week long “Čigotica” treatment. Thus far, two groups of adolescents of both sexes have emerged – the ones with marked weight loss and the significantly less responsive ones. By analyzing the differences in gut microbiota composition functionality between subjects with different weight loss efficiency, we hope we will be able to single out specific microbial taxa with crucial influence on the weight loss capacity. The corresponding in silico functional predictions we would make could then steer our further studies in an animal model of diet-induced obesity and finally enable us to reach key mechanistic insights into the microbial involvement in weight loss. In the near future, this could lead to the invention, patenting and production of the microbiome-based, probiotic-supplemented, specifically weight-loss stimulating therapies to combat obesity as one of the fastest-growing medical issues worldwide.
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