CEBR1-09
Obesity: Adipocyte signaling and potential therapeutic approaches
Researchers:
Dr. Assim A. Al-Fadda
Dr. Amr S. Mous
Dr. Reem M. Sallam
Dr. Muhammad Azhar Chishti
Dr. Khalid A. Al-Regaiey
Dr. Mohammed A. Alzoghaibi
ABSTRACT:
Obesity: Adipocyte signaling and potential therapeutic approaches
Obesity and associated disorders now constitute a serious threat to the current and future health of the human being worldwide. Approximately, 300 million are clinically obese worldwide. Obesity is associated with an array of additional health problems, including increased risk for insulin resistance, type 2 diabetes mellitus (T2DM), atherosclerosis, hypertension, and some cancers. This cluster of pathologies has also started to emerge in children at young ages, a particularly alarming and dangerous phenomenon. There is, therefore, an urgent need for finding new approaches to address obesity and associated diseases.
Obesity and related disorders are closely associated with chronic inflammation characterized by abnormal cytokine production, increased acute-phase reactants and activation of a network of signaling pathways. In addition, recent studies have documented the unusual properties of adipocytes, derived especially from visceral fat, as a crucial site in the generation of proinflammatory mediators and as a key site for interactions with different effectors of the immune system, including T-cells and macrophages. Several mechanisms have been postulated to explain how the inflammatory signals can mediate insulin resistance in obesity. A currently suggested molecular mechanism is through the increase in stress signaling. Stress signaling pathways constitute phosphorylation-based activation of kinases in response to different intracellular and extracellular stimuli, including inflammatory cytokines, oxidative stress, endoplasmic reticulum stress and hypertonic stress. Such kinases, in turn, phosphorylate various protein substrates on seine/threonine residues, thereby altering their function, cellular localization and/or protein stability.
The aim of this project is to study different signaling pathways in obesity and to define the sites and nature of the cross-talk between chemerin, adiponectin, MAP kinases and insulin signaling molecules. This would allow better understanding of the molecular basis of obesity and related diseases. Testing and validating new therapeutic approaches in animal models for treatment and prevention of obesity based on interfering with the defective mechanisms would be the optimum goal.
The study will be conducted on a total of 300 human subjects divided into 4 main groups, namely obese, obese and impaired glucose tolerance (IGT), obese and T2DM, and a group of healthy controls. Serum levels of studied adipocytokines will be measured by ELISA and for the active C-terminal part of chemerin by mass spectrometry. Primary culture of mature fat cells will be prepared from both visceral and subcutaneous adipose tissue. Real-time PCR will be used for evaluation of gene expression of adipokines at the RNA level. Western blotting and immunoprecipitation will be used for analysis of gene expression of adipokines at the protein level and for studying their phosphorylation status. In addition, purification of different forms of adiponectin and examining the role of each form in adipogenesis and obesity will be performed.
In conclusions, the understand of various processes that give rise to the cluster of the metabolic syndrome; from abnormal regulation of energy metabolism, to aberrant signaling pathways and dysfunction of molecular mechanisms; would lead to the development of new treatment strategies and establishment of preventive measures for obesity and its related disorders. In addition, this project will be the keystone for the establishment of a high standard, multidisciplinary research group for the transfer and development of biotechnology and its application in obesity research.
OBJECTIVES:
- To study the interactions and cross-talk between chemerin, adiponectin, MAP kinases and insulin signaling pathways during different phases of adipocyte differentiation in visceral and peripheral adipose tissue in lean and obese subjects.
- To study the profile of the inflammatory and oxidative stress markers, both in lean and obese subjects.
- To study the role of AMP-activated protein kinase and different phosphorylation events in the regulation of whole-body energy balance.
- To design new therapeutic measures for the prevention and treatment of obesity and its related disorders.