Adipose-specific disruption of autotaxin enhances nutritional fattening and reduces plasma lysophosphatidic acid

Abstract

Autotaxin (ATX) is a secreted lysophospholipase D that catalyzes the hydrolysis of lysophosphatidylcholine into lysophosphatidic acid (LPA), a growth factor-like lipid mediator acting via specifi c G-protein coupled receptors ( 1-3 ). ATX is present in plasma and other biological fl uids and is expressed by several organs and tissues but the tissue origin of circulating LPA remains unknown. ATX plays a crucial role in embryonic development because its knockout in mice is lethal due to impaired blood vessel formation and a failure of neural tube closure ( 4-6 ).So far, ATX has mostly been studied for its role in tumorigenesis, angiogenesis, and metastasis ( 7 ). Our group has brought ATX into the area of metabolic diseases. We have shown that ATX is abundantly expressed and secreted by adipocytes ( 8-10 ) and is responsible for the production of LPA in adipose tissue extracellular medium ( 11 ). Nevertheless, the specifi c contribution of adipose-ATX to circulating LPA remains unknown. ATX expression is increased in adipose tissue from obese/insulin-resistant mice and humans ( 9, 12 ). In vitro, ATX expression and secretion increase during the differentiation of preadipocytes into adipocytes (adipogenesis) ( 8, 9 ). These observations suggested that ATX contributes to fat development in obesity and associated pathologies. In the present study, we set out to disrupt ATX expression specifi cally in mouse adipose tissue to examine whether fat mass and plasma LPA concentration were affected. We demonstrate that adipocyte-specifi c disruption of ATX signifi cantly increases the sensitivity of adipose tissue to expand in response to a high-fat diet (HFD) and directly infl uences plasma LPA levels. Abstract Autotaxin (ATX) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA). ATX is secreted by adipose tissue and its expression is enhanced in obese/insulin-resistant individuals.Here, we analyzed the specifi c contribution of adipose-ATX to fat expansion associated with nutritional obesity and its consequences on plasma LPA levels. We established ATX

Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice

“…1a). This was in agreement with our previous report [19]. To investigate the possible involvement of LPA in the glucose intolerance of HFD mice, glucose tolerance tests were performed 30 min after a single injection of LPA.…”

“…The expression of ATX is increased in the adipose tissue of obese insulin-resistant individuals and mice [16][17][18]. Plasma levels of LPA are increased in high-fat diet (HFD) obese mice as the result of an increased expression of ATX in adipocytes [19]. Invalidation of ATX in adipocytes (FATX-KO mice) reduces plasma LPA and enhances fat mass in HFD-fed mice [19], in agreement with the anti-adipogenic effect of LPA [20].…”

“…We previously reported that transgenic-mediated reduction of LPA synthesis was associated with improved glucose tolerance in HFD-fed mice [19], suggesting that LPA has a negative impact on glucose homeostasis. Here we strengthened this hypothesis by showing the deleterious effect of LPA on glucose tolerance through inhibition of insulin secretion and we demonstrated that chronic pharmacological blockade of LPA receptors with Ki16425 can reverse the deterioration in glucose homeostasis in HFD obese prediabetic mice.…”

“…Plasma leptin and adiponectin were determined using Quantkine Immunoassays (R&D Systems, Minneapolis, MN, USA). Plasma LPA was measured using a radioenzymatic assay as previously Blood glucose described [19,27]. Briefly, lipids were extracted from conditioned media or plasma with an equal volume of 1-butanol and evaporated.…”

“…Interestingly, in vivo deletion of ATX in adipocytes (FATX-KO mice) is associated with a better glucose tolerance [19], suggesting a negative effect of LPA on glucose homeostasis. If this hypothesis is correct, LPA receptors could represent valuable pharmacological targets for the treatment of impaired glucose homeostasis associated with obesity.…”