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

Aims/hypothesis Lysophosphatidic acid (LPA) is a lipid mediator produced by adipocytes that acts via specific Gprotein-coupled receptors; its synthesis is modulated in obesity. We previously reported that reducing adipocyte LPA production in high-fat diet (HFD)-fed obese mice is associated with improved glucose tolerance, suggesting a negative impact of LPA on glucose homeostasis. Here, our aim was to test this hypothesis. Methods First, glucose tolerance and plasma insulin were assessed after acute (30 min) injection of LPA (50 mg/kg) or of the LPA1/LPA3 receptor antagonist Ki16425 (5 mgkg −1 day −1 , i.p.) in non-obese mice fed a normal diet (ND) and in obese/prediabetic (defined as glucose-intolerant) HFD mice. Glucose and insulin tolerance, pancreas morphology, glycogen storage, glucose oxidation and glucose transport were then studied after chronic treatment (3 weeks) of HFD mice with Ki16425. Results In ND and HFD mice, LPA acutely impaired glucose tolerance by inhibiting glucose-induced insulin secretion. These effects were blocked by pre-injection of Ki16425 (5 mg/kg, i.p.). Inhibition of glucoseinduced insulin secretion by LPA also occurred in isolated mouse islets. Plasma LPA was higher in HFD mice than in ND mice and Ki16425 transiently improved glucose tolerance. The beneficial effect of Ki16425 became permanent after chronic treatment and was associated with increased pancreatic islet mass and higher fasting insulinaemia. Chronic treatment with Ki16425 also improved insulin tolerance and increased liver glycogen storage and basal glucose use in skeletal muscle. Conclusions/interpretation Exogenous and endogenous LPA exerts a deleterious effect on glucose disposal through a reduction of plasma insulin; pharmacological blockade of LPA receptors improves glucose homeostasis in obese/prediabetic mice.