Obesity and obesity-related cardiovascular complications are an increasing health burden in the United States. An analysis of nearly 2 million veterans receiving care at VA Medical Centers in 2000 indicated that ~68% were overweight and ~37% were obese. Despite extensive investigation, viable therapeutic strategies to prevent weight gain or promote weight loss remain largely elusive. Attention has recently focused on the exciting possibility that a therapeutic strategy aimed at promoting energy expenditure by increasing brown adipose tissue (BAT) content or activity in adults could reduce fat deposition and obesity. However, such a therapeutic strategy requires a comprehensive understanding of factors that regulate BAT. Lysophosphatidic acid (LPA) is a bioactive lipid present in physiologically relevant levels in plasma and other biologic fluids and is positioned to play a role in human health and disease. The secreted lysophospholipase D autotaxin (autotaxin/lysoLPD) is responsible for production of extracellular, biologically active LPA, which is in turn inactivated by enxymatic dephosphorylation by lipid phosphate phosphatases (LPP). We provide evidence that treatment of primary cultures of preadipocytes with LPA or autotaxin reduces expression of markers of brown adipocyte differentiation and LPP3, an endogenous regulator of Wnt;whereas a novel autotaxin/lysoPLD inhibitor dramatically promotes brown adipocyte differentiation. In mice, overexpression of autotaxin reduces UCP1 expression and promotes diet-induced obesity. We therefore propose the central hypothesis that signaling pathways regulated by autotaxin and LPP3 contribute to diet-induced thermogenesis and regulate the development of diet-induced obesity. We will test our central hypothesis using state-of-the art genetic and pharmacologic approaches in three specific aims.
In Aim One, we will identify the role of autotaxin/lysoPLD in regulation of brown adipose tissue and diet-induced obesity in animal models.
In Aim Two, we will establish the molecular mechanism(s) by which LPA and autotaxin exert their effects.
In Aim Three, we identify the role of LPP3 in development and function of adipose tissue and diet-induced obesity.
The aims of this grant provide a vehicle to address a major unresolved issue in the field of lysolipid signaling, namely role of autotaxin/lysoPLD, LPA, and LPP3 in regulation of adiposity. These results will be significant, because they are expected to provide innovative targets and provide proof-of-concept for novel inhibitors that may be used for prevention and treatment of obesity in humans.

Public Health Relevance

Project Narrative More than 44 million Americans are obese, as defined by body mass index (BMI) of >30 kg/m2. Obesity is a significant health care problem among veterans receiving care at VA Medical Centers. A comprehensive analysis of nearly 2 million veterans in 2000 indicated that ~68% were overweight and ~37% were obese. Current strategies to treat and prevent obesity focus primarily on reducing energy consumption through appetite suppression and behavioral modification. Recent attention has focused on an attractive alternative approach, namely that of increasing energy expenditure by enhancing the heat-dissipating function of brown adipose tissue in adults. We provide evidence that the secreted lysophospholipase D autotaxin, responsible for production of biologically active LPA, may regulate the functional status of brown adipose tissue. The goal of the current study is to identify the role of the autotaxin/LPA signaling nexus in the regulation of adipose tissue and diet-induced obesity. Our results may suggest innovative targets to prevent and treat obesity in humans.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Endocriniology A (ENDA)
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VA Medical Center - Lexington, KY
United States
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Morris, Andrew J; Smyth, Susan S (2016) Regulation of Lysophosphatidic Acid Metabolism and Signaling by Lipoproteins. Arterioscler Thromb Vasc Biol 36:2029-30
Abdel-Latif, Ahmed; Heron, Paula M; Morris, Andrew J et al. (2015) Lysophospholipids in coronary artery and chronic ischemic heart disease. Curr Opin Lipidol 26:432-7
Wu, Tao; Kooi, Craig Vander; Shah, Pritom et al. (2014) Integrin-mediated cell surface recruitment of autotaxin promotes persistent directional cell migration. FASEB J 28:861-70
Panchatcharam, Manikandan; Salous, Abdel K; Brandon, Jason et al. (2014) Mice with targeted inactivation of ppap2b in endothelial and hematopoietic cells display enhanced vascular inflammation and permeability. Arterioscler Thromb Vasc Biol 34:837-45
Smyth, Susan S; Mueller, Paul; Yang, Fanmuyi et al. (2014) Arguing the case for the autotaxin-lysophosphatidic acid-lipid phosphate phosphatase 3-signaling nexus in the development and complications of atherosclerosis. Arterioscler Thromb Vasc Biol 34:479-86
Salous, Abdel K; Panchatcharam, Manikandan; Sunkara, Manjula et al. (2013) Mechanism of rapid elimination of lysophosphatidic acid and related lipids from the circulation of mice. J Lipid Res 54:2775-84