Adipocyte ATGL-mediated lipolysis in systemic insulin action

Obesity is a global health problem that is highly associated with additional metabolic abnormalities including insulin resistance, glucose intolerance, hypertension, and dyslipidemia. The combination of these abnormalities, known as the metabolic syndrome is a major contributor to morbidity and mortality from a variety of diseases affecting virtually all organ systems. Obesity is essentially a disorder of excess lipid accumulation, primarily in the form of triacylglycerols (TGs) in adipose tissue. In the setting of chronic energy excess, adipose tissue TG storage capacity becomes overwhelmed, resulting in adipose tissue dysfunction, enhanced lipolysis (and ectopic lipid accumulation), and inflammation - ultimately contributing to systemic metabolic disease. Hence, understanding the major determinant of adipose tissue TG storage and function are of considerable biomedical importance for identifying effective therapies for obesity and the metabolic syndrome. Adipose triglyceride lipase (ATGL) has recently been identified as the rate-limiting enzyme mediating TG hydrolysis, and is therefore a critical determinant of adipocyte TG storage/hydrolysis. ATGL deficiency in mice (and humans) results in severe metabolic dysfunction characterized by abnormal glucose/lipid homeostasis, fatty liver disease, myopathy, and cardiomyopathy. However, the contribution of adipocyte-specific ATGL-mediated TG hydrolysis to this phenotype is unknown and difficult to determine given the severe morbidity and early mortality associated with global ATGL deficiency. To overcome this issue, we have generated mice with adipocyte-specific targeted deletion of ATGL (adipose-specific ATGL knockout or "AAKO" mice). The CENTRAL AIM of this proposal is to determine the contribution of adipocyte-specific ATGL-mediated TG hydrolysis to adipose tissue function, insulin responsiveness, and inflammation in vivo. Our HYPOTHESIS is that adipocyte-specific ATGL deletion will protect against adipose tissue dysfunction, insulin resistance, and inflammation, thereby improving systemic metabolic homeostasis despite increased adiposity. To test this hypothesis, we propose three specific aims. In AIM 1, we will determine the contribution of adipocyte ATGL to systemic energy and lipid homeostasis by performing comprehensive metabolic evaluation of AAKO mice. We will further specifically define the intracellular lipid phenotype in metabolically-relevant tissues (adipose tissue, liver, skeletal muscle). In AIM 2, we will elucidate the contribution of adipocyte ATGL to glucose homeostasis and insulin responsiveness in AAKO mice by evaluating glucose uptake and insulin signaling in vivo and ex vivo in metabolically-relevant tissues and by performing hyperinsulinemic-euglycemic clamp studies. In AIM 3, we will analyze the contribution adipocyte ATGL to inflammation in adipose tissue (as well other tissues) of AAKO mice by evaluating inflammatory genes/pathways and infiltration by mononuclear cells. These studies will promote the understanding of ATGL in adipocyte-specific and systemic metabolism, thereby providing important insights into the pathogenesis and treatment of obesity and related metabolic disorders.