title: Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice.
abstract: OBJECTIVE
  Lysophosphatidic acid (LPA) is a lipid mediator produced by adipocytes that acts via specific G-protein-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 mg kg(-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 glucose-induced 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
  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.
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Université Paul Sabaties, Inserm U1048, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France.
authors.forename: C
authors.initials: C
authors.lastname: Rancoule
authors.forename: C
authors.initials: C
authors.lastname: Attané
authors.forename: S
authors.initials: S
authors.lastname: Grès
authors.forename: A
authors.initials: A
authors.lastname: Fournel
authors.forename: R
authors.initials: R
authors.lastname: Dusaulcy
authors.forename: C
authors.initials: C
authors.lastname: Bertrand
authors.forename: C
authors.initials: C
authors.lastname: Vinel
authors.forename: K
authors.initials: K
authors.lastname: Tréguer
authors.forename: M
authors.initials: M
authors.lastname: Prentki
authors.forename: P
authors.initials: P
authors.lastname: Valet
authors.forename: J S
authors.initials: JS
authors.lastname: Saulnier-Blache
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000818:Animals; D001835:Body Weight; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007555:Isoxazoles / Q000494:pharmacology; D008055:Lipids / Q000737:chemistry; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D013997:Time Factors
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D007328:Insulin; D007555:Isoxazoles; D008055:Lipids; D008246:Lysophospholipids; D011422:Propionates; D006003:Glycogen; D005947:Glucose; C032881:lysophosphatidic acid; D010100:Oxygen