Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes.
To elucidate the function of PPARgamma in leptin-deficient mouse (ob/ob) liver, a PPARgamma liver-null mouse on an ob/ob background, ob/ob-PPARgamma(fl/fl)AlbCre(+), was produced using a floxed PPARgamma allele, PPARgamma(fl/fl), and Cre recombinase under control of the albumin promoter (AlbCre). The liver of ob/ob-PPARgamma(fl/fl)AlbCre(+) mice had a deletion of exon 2 and a corresponding loss of full-length PPARgamma mRNA and protein. The PPARgamma-deficient liver in ob/ob mice was smaller and had a dramatically decreased triglyceride (TG) content compared with equivalent mice lacking the AlbCre transgene (ob/ob-PPARgamma(fl/fl)AlbCre(-)). Messenger RNA levels of the hepatic lipogenic genes, fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase-1, were reduced in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice, and the levels of serum TG and FFA in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice were significantly higher than in the control ob/ob-PPARgamma(fl/fl)AlbCre(-) mice. Rosiglitazone treatment exacerbated the fatty liver in ob/ob-PPARgamma(fl/fl)AlbCre(-) mice compared with livers from nonobese Cre(-) mice; there was no effect of rosiglitazone in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice. The deficiency of hepatic PPARgamma further aggravated the severity of diabetes in ob/ob mice due to decreased insulin sensitivity in muscle and fat. These data indicate that hepatic PPARgamma plays a critical role in the regulation of TG content and in the homeostasis of blood glucose and insulin resistance in steatotic diabetic mice.
Matsusue
Kimihiko
K
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Frederick, Maryland 20892, USA.
Haluzik
Martin
M
Lambert
Gilles
G
Yim
Sun-Hee
SH
Gavrilova
Oksana
O
Ward
Jerrold M
JM
Brewer
Bryan
B
Reitman
Marc L
ML
Gonzalez
Frank J
FJ
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000209:etiology* / Q000628:therapy; D006943:Hyperglycemia / Q000209:etiology*; D007333:Insulin Resistance; D020738:Leptin / Q000172:deficiency*; D008071:Lipoprotein Lipase / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011973:Receptors, LDL / Q000378:metabolism; D054411:Receptors, Leptin; D000077154:Rosiglitazone; D013844:Thiazoles / Q000627:therapeutic use; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D020738:Leptin; D008079:Lipoproteins, VLDL; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D054411:Receptors, Leptin; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; C515447:leptin receptor, mouse; D000077154:Rosiglitazone; D008071:Lipoprotein Lipase