Obesity and the metabolic syndrome are global health threats. Intracellular triacylglycerol (TG) accumulation is strongly associated with insulin resistance and metabolic complications of obesity. However, the mechanisms underlying TG accumulation and its relationship to lipid-induced toxic metabolic effects ("lipotoxicity") remain unclear. Emerging evidence suggests that non-TG lipid metabolites (i.e. diacylglycerols, ceramides, fatty-acyl CoAs, etc.) rather than TGs themselves are pathogenic for these disorders, indicating that interventions designed to enhance TG storage and/or reduce production of "toxic" lipid metabolites may protect against insulin resistance and lipotoxic metabolic disease. Adipose triglyceride lipase (ATGL) has recently been identified as the rate-limiting enzyme mediating TG hydrolysis, and is therefore a critical determinant of storage/production of toxic as well as essential lipid metabolites. Nevertheless, the role of ATGL in these processes, particularly in non-adipose tissues where ATGL is also expressed, remains poorly understood. Our preliminary data suggest that i) ATGL is expressed, highly regulated, and functionally relevant in adipose and non-adipose tissues, and ii) modulation of ATGL-mediated TG hydrolysis influences glucose homeostasis/ insulin action in vitro and in vivo in a tissue/cell type-specific manner. Understanding the relative contribution of ATGL in individual tissues to overall metabolic homeostasis in vivo as well as the mechanisms by which ATGL exerts these effects are essential for determining whether TG metabolism can be therapeutically modulated to protect against lipotoxic metabolic disease. The CENTRAL AIM of this proposal is to determine the tissue- specific contribution of ATGL-mediated TG hydrolysis in metabolically relevant tissues (adipose tissue and skeletal muscle) to lipotoxicity and the metabolic syndrome in vivo using genetically-engineered mice as model systems. Our OVERALL HYPOTHESIS is that dysregulation of ATGL-mediated TG hydrolysis, by modulating intracellular lipid homeostasis, is a major determinant of both tissue-specific and systemic glucose homeostasis/insulin action. To test this hypothesis, we will evaluate local and systemic lipid homeostasis and glucose homeostasis/insulin action in mice with tissue-specific modulation of ATGL in adipose tissue (AIM 1) and skeletal muscle (AIM 2). We will further define the molecular mechanisms by which modulation of ATGL alters lipid homeostasis and glucose homeostasis/insulin action by evaluating specific mechanisms that contribute to lipotoxicity (i.e. endoplasmic reticulum stress, mitochondrial dysfunction, inflammation, etc.). These studies will promote the understanding of ATGL in tissue-specific and systemic metabolism, thereby providing important insights into the pathogenesis and treatment of obesity and related metabolic disorders. This is the first R01 application of an early stage investigator.
Accumulation of fat in adipose and non-adipose tissues (i.e. muscle) is associated with complications of obesity including diabetes and cardiovascular disease. Adipose triglyceride lipase (ATGL) is a newly identified enzyme that breaks down fat, but the contribution of fat breakdown by this enzyme in specific individual tissues to whole body metabolism is not known. Understanding the physiological relevance and mechanistic underpinnings of tissue-specific ATGL-mediated fat breakdown will provide important insights into the pathophysiology and treatment of obesity and related metabolic disorders.
|Minster, Ryan L; Hawley, Nicola L; Su, Chi-Ting et al. (2016) A thrifty variant in CREBRF strongly influences body mass index in Samoans. Nat Genet 48:1049-54|
|Edmunds, Lia R; Otero, P Anthony; Sharma, Lokendra et al. (2016) Abnormal lipid processing but normal long-term repopulation potential of myc-/- hepatocytes. Oncotarget 7:30379-95|
|Reeves, Valerie L; Trybula, Joy S; Wills, Rachel C et al. (2015) Serum Autotaxin/ENPP2 correlates with insulin resistance in older humans with obesity. Obesity (Silver Spring) 23:2371-6|
|Kokai, Lauren E; Marra, Kacey G; Kershaw, Erin E (2015) Three-Dimensional Adipocyte Culture: The Next Frontier for Adipocyte Biology Discovery. Endocrinology 156:4375-6|
|Schlager, Stefanie; Goeritzer, Madeleine; Jandl, Katharina et al. (2015) Adipose triglyceride lipase acts on neutrophil lipid droplets to regulate substrate availability for lipid mediator synthesis. J Leukoc Biol 98:837-50|
|Foryst-Ludwig, Anna; Kreissl, Michael C; Benz, Verena et al. (2015) Adipose Tissue Lipolysis Promotes Exercise-induced Cardiac Hypertrophy Involving the Lipokine C16:1n7-Palmitoleate. J Biol Chem 290:23603-15|
|Rachakonda, Vikrant P; Reeves, Valerie L; Aljammal, Jules et al. (2015) Serum autotaxin is independently associated with hepatic steatosis in women with severe obesity. Obesity (Silver Spring) 23:965-72|
|DubÃ©, John J; Sitnick, Mitch T; Schoiswohl, Gabriele et al. (2015) Adipose triglyceride lipase deletion from adipocytes, but not skeletal myocytes, impairs acute exercise performance in mice. Am J Physiol Endocrinol Metab 308:E879-90|
|Schoiswohl, Gabriele; Stefanovic-Racic, Maja; Menke, Marie N et al. (2015) Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice. Endocrinology 156:3610-24|
|Mottillo, Emilio P; Balasubramanian, Priya; Lee, Yun-Hee et al. (2014) Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic Î²3-adrenergic receptor activation. J Lipid Res 55:2276-86|
Showing the most recent 10 out of 16 publications