title: The proton-activated receptor GPR4 modulates glucose homeostasis by increasing insulin sensitivity.
abstract: BACKGROUND
  The proton-activated G protein-coupled receptor GPR4 is expressed in many tissues including white adipose tissue. GPR4 is activated by extracellular protons in the physiological pH range (i.e. pH 7.7 - 6.8) and is coupled to the production of cAMP.
  
  
  METHODS
  We examined mice lacking GPR4 and examined glucose tolerance and insulin sensitivity in young and aged mice as well as in mice fed with a high fat diet. Expression profiles of pro- and anti-inflammatory cytokines in white adipose tissue, liver and skeletal muscle was assessed.
  
  
  RESULTS
  Here we show that mice lacking GPR4 have an improved intraperitoneal glucose tolerance test and increased insulin sensitivity. Insulin levels were comparable but leptin levels were increased in GPR4 KO mice. Gpr4-/- showed altered expression of PPARa, IL-6, IL-10, TNFa, and TGF-1b in skeletal muscle, white adipose tissue, and liver. High fat diet abolished the differences in glucose tolerance and insulin sensitivity between Gpr4+/+ and Gpr4-/- mice. In contrast, in aged mice (12 months old), the positive effect of GPR4 deficiency on glucose tolerance and insulin sensitivity was maintained. Liver and adipose tissue showed no major differences in the mRNA expression of pro- and anti-inflammatory factors between aged mice of both genotypes.
  
  
  CONCLUSIONS
  Thus, GPR4 deficiency improves glucose tolerance and insulin sensitivity. The effect may involve an altered balance between pro- and anti-inflammatory factors in insulin target tissues.
authors.forename: Luca
authors.initials: L
authors.lastname: Giudici
authors.forename: Ana
authors.initials: A
authors.lastname: Velic
authors.forename: Arezoo
authors.initials: A
authors.lastname: Daryadel
authors.forename: Carla
authors.initials: C
authors.lastname: Bettoni
authors.forename: Nilufar
authors.initials: N
authors.lastname: Mohebbi
authors.forename: Thomas
authors.initials: T
authors.lastname: Suply
authors.forename: Klaus
authors.initials: K
authors.lastname: Seuwen
authors.forename: Marie-Gabrielle
authors.initials: MG
authors.lastname: Ludwig
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000375:Aging; D000818:Animals; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006863:Hydrogen-Ion Concentration; D007333:Insulin Resistance / Q000502:physiology*; D016753:Interleukin-10 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000235:genetics; D047493:PPAR alpha / Q000235:genetics; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D011522:Protons; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D015850:Interleukin-6; D047493:PPAR alpha; D011522:Protons; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases; D005947:Glucose