Abstract
Besides serving as a structural membrane component and intermediate of the glycerolipid metabolism, lysophosphatidic acid (LPA) has a prominent role as a signaling molecule through its binding to LPA receptors at the cell surface. Extracellular LPA is primarily produced from lysophosphatidylcholine (LPC) through the activity of secreted lysophospholipase D, autotaxin (ATX). The degradation of extracellular LPA to monoacylglycerol is mediated by lipid phosphate phosphatases (LPPs) at the cell membrane. This review summarizes and interprets current literature on the role of the ATX-LPA-LPP3 axis in the regulation of energy homeostasis, insulin function, and adiposity at baseline and under conditions of obesity. We also discuss how the ATX-LPA-LPP3 axis influences obesity-related metabolic complications, including insulin resistance, fatty liver disease, and cardiomyopathy.
Highlights
IntroductionThe obesity epidemic presents a worldwide health crisis. The disruption in energy homeostasis during obesity predisposes to insulin resistance and type 2 diabetes mellitus (T2DM)
Autotaxin-lysophosphatidic acid (LPA)-LPP3 Axis in EnergyThe obesity epidemic presents a worldwide health crisis
We summarize and interpret studies examining the role of ATX, LPA receptors, and LPP3 in energy homeostasis and insulin function with an emphasis on diet-induced obesity
Summary
The obesity epidemic presents a worldwide health crisis. The disruption in energy homeostasis during obesity predisposes to insulin resistance and type 2 diabetes mellitus (T2DM). Male C57Bl6/J mice fed a high fat (60% or 45% kcal fat) diet for eight or nine weeks had increased plasma LPA [33–35 and adipose ATX mRNA levels [33]. Mice with liver-specific LPP3 deficiency on an apolipoprotein E knockout background have increased plasma LPA levels when fed a Western diet [28]. We summarize and interpret studies examining the role of ATX, LPA receptors, and LPP3 in energy homeostasis and insulin function with an emphasis on diet-induced obesity. This article complements prior reviews on the role of the ATX-LPA signaling axis in obesity and impaired glucose homeostasis [9,32] while including many more recent studies and expanding the scope to discuss the involvement of LPP3 in glucose homeostasis and the ATX-LPA-LPP3 axis in metabolic cardiomyopathy
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