title: A new, highly selective murine peroxisome proliferator-activated receptor δ agonist increases responsiveness to thermogenic stimuli and glucose uptake in skeletal muscle in obese mice.
abstract: OBJECTIVE
  We investigated how GW800644, the first pharmacologically selective murine peroxisome proliferator-activated receptor δ (PPARδ) agonist, affects energy balance, glucose homeostasis and fuel utilization by muscle in obese mice.
  
  
  METHODS
  Potencies were determined in transactivation assays. Oral glucose tolerance was determined after 14 and 22 days' administration (10 mg/kg body weight, twice daily) to Lep(ob)/Lep(ob) mice. Food intake and energy expenditure were measured during a 26-day experiment, and plasma metabolites and 2-deoxyglucose uptake in vivo at termination. Palmitate oxidation and 2-deoxyglucose uptake by isolated soleus muscles were measured after 14 (in lean and obese mice) and 26 days.
  
  
  RESULTS
  GW800644 activated murine PPARδ (EC(50) 2 nM), but caused little to no activation of PPARα or PPARγ up to 10 µM. It did not increase liver weight. GW800644 reduced food intake and body weight in obese mice after 8 days. It did not affect resting energy expenditure, but, compared to pair-fed mice, it increased the response to a β(3)-adrenoceptor agonist. It improved glucose tolerance. GW800644, but not pair-feeding, reduced plasma glucose, insulin and triglyceride concentrations. It increased 2-deoxyglucose uptake in vivo in adipose tissue, soleus muscle, heart, brain and liver, and doubled 2-deoxyglucose uptake and palmitate oxidation in isolated soleus muscle from obese but not lean mice.
  
  
  CONCLUSIONS
  PPARδ agonism reduced food intake and independently elicited metabolic effects that included increased responsiveness to β(3)-adrenoceptor stimulation, increased glucose utilization and fat oxidation in soleus muscle of Lep(ob)/Lep(ob) but not lean mice and increased glucose utilization in vivo in Lep(ob)/Lep(ob) mice.
authors.affiliation: Clore Laboratory, University of Buckingham, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Ngala
authors.forename: C J
authors.initials: CJ
authors.lastname: Stocker
authors.forename: A G
authors.initials: AG
authors.lastname: Roy
authors.forename: D
authors.initials: D
authors.lastname: Hislop
authors.forename: E
authors.initials: E
authors.lastname: Wargent
authors.forename: R
authors.initials: R
authors.lastname: Bell
authors.forename: D G
authors.initials: DG
authors.lastname: Hassall
authors.forename: J D
authors.initials: JD
authors.lastname: Harling
authors.forename: A N
authors.initials: AN
authors.lastname: Billin
authors.forename: T M
authors.initials: TM
authors.lastname: Willson
authors.forename: J R S
authors.initials: JR
authors.lastname: Arch
authors.forename: M A
authors.initials: MA
authors.lastname: Cawthorne
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists*; D010642:Phenoxyacetates; D011725:Pyridines / Q000494:pharmacology*; D022722:Thermogenesis; D013997:Time Factors
chemical_list: C569099:2-(2-methyl-4-((1-(6-(4-(trifluoromethyl)phenyl)-2-pyridinyl)pentyl)oxy)phenoxy)acetic acid; D000085:Acetates; D047494:PPAR delta; D010642:Phenoxyacetates; D011725:Pyridines; D005947:Glucose