WY14,643, a peroxisome proliferator-activated receptor alpha (PPARalpha ) agonist, improves hepatic and muscle steatosis and reverses insulin resistance in lipoatrophic A-ZIP/F-1 mice.
WY14,643 is a specific peroxisome proliferator-activated receptor alpha (PPARalpha) agonist with strong hypolipidemic effects. Here we have examined the effect of WY14,643 in the A-ZIP/F-1 mouse, a model of severe lipoatrophic diabetes. With 1 week of treatment, all doses of WY14,643 that were tested normalized serum triglyceride and fatty acid levels. Glucose and insulin levels also improved but only with high doses and longer treatment duration. WY14,643 reduced liver and muscle triglyceride content and increased levels of mRNA encoding fatty acid oxidation enzymes. In liver, the elevated lipogenic mRNA profile (including PPARgamma) in A-ZIP/F-1 mice remained unchanged. These results suggest that WY14,643 acts by increasing beta-oxidation rather by than decreasing lipogenesis or lipid uptake. Hyperinsulinemic euglycemic clamp studies indicated that WY14,643 treatment improved liver more than muscle insulin sensitivity and that hepatic mRNA levels of gluconeogenic enzymes were reduced. Combination treatment with both WY14,643 and a PPARgamma ligand, rosiglitazone, did not lower glucose levels more effectively than did treatment with WY14,643 alone. These data support the hypothesis that reducing intracellular triglycerides in non-adipose tissues improves insulin sensitivity and suggest that further investigation of the role of PPARalpha agonists in the treatment of lipoatrophic diabetes is warranted.
Chou
Chieh J
CJ
Diabetes Branch, NIDDK and the Metabolism Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Haluzik
Martin
M
Gregory
Charmaine
C
Dietz
Kelly R
KR
Vinson
Charles
C
Gavrilova
Oksana
O
Reitman
Marc L
ML
D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003923:Diabetes Mellitus, Lipoatrophic / Q000235:genetics*; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D051275:Glucose Transporter Type 4; D006006:Glycogen Synthase / Q000235:genetics; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology*; D009336:Necrosis; D011743:Pyrimidines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014280:Triglycerides / Q000097:blood*
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; D000960:Hypolipidemic Agents; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; D014280:Triglycerides; C006253:pirinixic acid; D006006:Glycogen Synthase; D000103:Acetyl-CoA Carboxylase