Impact of insulin resistance on trafficking and signaling of beta-3 adrenergic receptor in adipocytes

Project Summary:

Obesity and Type 2 Diabetes are two of the biggest healthcare concerns of 21st century worldwide and particularly in the Kingdom of Saudi Arabia. Epidemiological studies have estimated that over 25% of adult population in the Kingdom of Saudi Arabia is suffering from diabetes and this figure is going to increase with time. The cost of treatment for diabetic patients in the Kingdom runs in billions of Riyals. In view of these alarming figures there is a need to embrace a multi-pronged approach to tackle this issue and employ strategies to find novel and innovative therapeutic targets that could lead to prevention and/or cure of obesity and Type 2 diabetes. Beta 3 Adrenergic receptor (β3-AR) has emerged as one of the prime candidates that could be targeted as a therapeutic remedy to obesity and type 2 diabetes. β3-AR are mainly expressed in white adipose tissue (WAT) and brown adipose tissue (BAT). Activation of β3-AR with selective agonists stimulates lipolysis and release of fatty acids in WAT and also activation of thermogenesis in BAT. Several studies have clearly and convincingly elucidated the role of β3-AR in metabolic homeostasis in animal models of obesity/type 2 diabetes and in human diabetic patients. Additional evidence has come from a naturally occurring missense mutants of β3AR (W64R, S165P and S257P) that has been shown to be associated with increased incidence of Type 2 diabetes in various studies.
Objectives: To understand molecular mechanism of agonist-induced trafficking, signaling and functioning of β3AR in fully differentiated adipocytes.
Methodology: The project will employ most current concepts in G-protein Coupled Receptor (GPCR) biology to study the behavior of β3AR in adipocytes. Throughout this application, I propose to use state-of-the-art methods that are appropriate for addressing some of the most significant questions regarding β3-AR biology. The study will use dual tagged reporter construct (HA- β3-AR-GFP) to track the movement of β3-AR using quantitative fluorescence and confocal microscopy. The behavior of β3AR will be studied in normal and in insulin-resistant adipocytes.
Possible outcome/benefits: Studies using molecular and biochemical techniques are likely to provide additional and novel insights into the functioning of β3AR in both normal physiology and disease. Understanding the detailed mechanism of β3AR function may lead to new therapeutic targets to prevent/cure obesity and type 2 diabetes mellitus.