Grant: Foundation Grant

Abhd6; Adipose Browning; Fuel Detoxification; Glycerol-3-Phosphatase; Glycerolipid/Free Fatty Acid Cycling; Insulin Secretion; Lipid Metabolism; Monoacylglycerol; Obesity; Pancreatic Beta Cell

<html> <body> <p>Type 2 diabetes (T2D) and obesity are multi-factorial diseases encompassing dysfunctions of pancreatic islet, liver and adipose tissues, insulin resistance and cardiometabolic complications. Current therapies for T2D and obesity address one aspect of the disease at a time, which often leads to long-term failure of these approaches. It is desirable to find target(s) allowing simultaneous correction of these multiple derangements by a single therapeutic intervention.<br> <br> In our studies on glycerolipid/ fatty acid (GL/FA) cycle, a key pathway balancing glucose and lipid metabolism, we discovered that GL/FA cycle-derived monoacylglycerol (MAG) is involved in insulin secretion and action, adipose browning and energy expenditure, and the regulation of appetite and locomotor activity. We also found that signaling-competent MAG levels are regulated by &#x03b1;/&#x03b2;-hydrolase domain 6 (ABHD6) that degrades this metabolite to glycerol and fatty acids. In addition, we recently discovered a novel metabolic enzyme in mammalian cells, glycerol-3-phosphate (Gro3P) phosphatase (G3PP), which controls cellular levels of Gro3P, a metabolite that lies at the intersection of glucose and glycerolipid metabolism. Our supporting data reveal that G3PP indeed regulates glucose and fatty acid metabolism at large and many physiological functions. The evidence also indicates that inhibition of ABHD6 or activation of G3PP has anti-diabetic and obesity effects.<br> <em> <br> The</em> <em>overall</em> <em>goals of this proposal are to:</em> <br> <em>-Define the role of two novel GL/FA cycle enzymes, ABHD6 and G3PP, in the regulation of insulin secretion and action, the control of adipose browning and energy homeostasis;<br> -Identify novel targets and functions of MAG as a second messenger;<br> -Harness this knowledge for the prevention and treatment of T2D and obesity.</em> <br> <br> The anticipated findings will:<br> -Emphasize the importance of GL/FA cycle and the new enzymes that control the exit (ABHD6) and entry (G3PP) of metabolites into the cycle in the overall regulation of energy homeostasis, fuel metabolism and detoxification.<br> -Delineate how these enzymes are regulated and control various biological functions.<br> -Address the question if ABHD6 can fulfill the role of a &ldquo;single&rdquo; target that can result in beneficial therapeutic effects against obesity, T2D, and &#x03b2;-cell dysfunction.<br> -Identify G3PP as a novel target, whose activation can be beneficial for metabolic derangements in different tissues in the context of fuel surfeit.<br> <br> The healthcare relevant impact and outcome will be to identify ABHD6 inhibitors and G3PP activators and to test their therapeutic efficacy for obesity, T2D and cardiovascular diseases, in collaboration with industrial partners.<br> <br> The proposed work calls for significant experience in metabolic and molecular studies, both <em>in vitro</em> and <em>in vivo,</em> that are accessible in the laboratory. This program will be undertaken by the PI and a team of senior investigators with years of experience in metabolic diseases, molecular &amp; cell biology and drug discovery &amp; development; collaborating experts in relevant fields; and well trained post docs, students and technicians. The trainees will be exposed to various aspects of translational research from mechanistic studies to drug discovery and development, which will provide them with a greater insight of medical research.</p> </body> </html>