Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass.
Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor that mediates the antidiabetic effects of thiazolidinediones. PPAR gamma is present in adipose tissue and becomes elevated in fatty livers, but the roles of specific tissues in thiazolidinedione actions are unclear. We studied the function of liver PPAR gamma in both lipoatrophic A-ZIP/F-1 (AZIP) and wild type mice. In AZIP mice, ablation of liver PPAR gamma reduced the hepatic steatosis but worsened the hyperlipidemia, triglyceride clearance, and muscle insulin resistance. Inactivation of AZIP liver PPAR gamma also abolished the hypoglycemic and hypolipidemic effects of rosiglitazone, demonstrating that, in the absence of adipose tissue, the liver is a primary and major site of thiazolidinedione action. In contrast, rosiglitazone remained effective in non-lipoatrophic mice lacking liver PPAR gamma, suggesting that adipose tissue is the major site of thiazolidinedione action in typical mice with adipose tissue. Interestingly, mice without liver PPAR gamma, but with adipose tissue, developed relative fat intolerance, increased adiposity, hyperlipidemia, and insulin resistance. Thus, liver PPAR gamma regulates triglyceride homeostasis, contributing to hepatic steatosis, but protecting other tissues from triglyceride accumulation and insulin resistance.
Gavrilova
Oksana
O
Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. oksanag@bdg10.niddk.nih.gov
Haluzik
Martin
M
Matsusue
Kimihiko
K
Cutson
Jaime J
JJ
Johnson
Lisa
L
Dietz
Kelly R
KR
Nicol
Christopher J
CJ
Vinson
Charles
C
Gonzalez
Frank J
FJ
Reitman
Marc L
ML
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D005260:Female; D007003:Hypoglycemia / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012313:RNA / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000502:physiology*; D011995:Recombination, Genetic; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism*
D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; D000077154:Rosiglitazone; D012313:RNA