Induction of white adipose tissue (WAT) browning could be a powerful tool for the treatment of metabolic diseases. However, there is a pressing need for innovative approaches focused not only on induction but on precise regulation of the browning process. Currently, there is a lack of data regarding the mechanisms of browning inhibition. As a result, the concept of therapeutic inhibition of browning is virtually non-existent. WARMED is aimed at developing new redox-based approaches to control brown adipocyte formation. WARMED could be a step forward, in an exciting effort to heal obese adipocytes by in vitro transdifferentiation and re-implantation in the host adipose tissue – as Trojan adipocytes to overcome metabolic diseases from inside. We will investigate the role of a small redox-active molecule, nitric oxide (NO) in WAT browning. The synthesis and signaling of NO will be pharmacologically modulated and browning will be investigated in animal models of cold acclimation and diabetes. To translate those finding and test for therapeutic relevance of WAT browning in obesity and tumorigenesis, molecular biomarkers of NO-directed WAT browning will be investigated in lean, obese and lipoma WAT. Finally, human primary adipocytes and adipose tissue-derived stem cells will be used to develop an in vitro model for NO-directed transdifferentiation. Such model would advance the basis for cell transplantation therapy and contribute to the understanding of the WAT browning in humans. Proposed topic is trans-disciplinary and demands a unique integration of approaches, competencies, and resources from molecular and cell biology, chemistry, physiology, and medicine. Such challenge is ideal for the development of new research directions since it utilizes existing disciplines and developed methodologies to tackle a new and exciting problem. Researches from four institutions across the Republic of Serbia will come together and form a new research group to tackle this intricate problem.
Using redox-based approaches to imitate naturally occurring cell signaling
Using knowledge of adipose tissue morpho-functional plasticity to transform adipocyte phenotype from energy-storing to energy-wasting.
Using in vitro transdifferentiated adipocytes as the basis of personalized cell therapy for obesity and metabolic diseases.
The main aim of WARMED is to develop methodology for NO-guided adipose tissue browning.
01. reveal NO-related biomarkers of WAT browning activation and inhibition
Identify NO-related biomarkers of browning activation and inhibition in cold acclimation and diabetes animal models and translate these findings to human adipose tissue, by analyzing adipose tissue of obese and lean individuals (as a model of impaired browning capacity) and lipoma tissue (as a model of unimpaired browning capacity).
02. direct browning of WAT by pharmacological modulation of NO, as an alternative to cold stimulation
Pharmacologically modulate NO level in WAT by increasing NO synthesis or NO bioavailability in animal models of cold acclimation and diabetes and test whether modulation of NO synthesis or NO bioavailability is the better approach to the regulation of browning in obesity/diabetes?
03. develop a model for in vitro NO-directed transdifferentiation of human primary adipocytes as the basis for autotransplantation therapy
Transdifferentiate primary adipocytes and adipose derived stem cells from obese subjects toward the beige adipocytes by NO level modulation.
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