Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones

There is uncertainty about the site(s) of action of the antidiabetic thiazo lidinediones (TZDs). These drugs are agonist ligands of the transcription f actor PPAR gamma, which is abundant in adipose tissue but is normally prese nt at very low levels in liver and muscle. We have studied the effects of T ZDs in A-ZIP/F-1 mice, which lack white adipose tissue. The A-ZIP/F-1 pheno type strikingly resembles that of humans with severe lipoatrophic diabetes, including the lack of fat, marked insulin resistance and hyperglycemia, hy perlipidemia, and fatty liver. Rosiglitazone or troglitazone treatment did not reduce glucose or insulin levels, suggesting that white adipose tissue is required for the antidiabetic effects of TZDs. However, TZD treatment wa s effective in lowering circulating triglycerides and increasing whole body fatty acid oxidation in the A-ZIP/F-1 mice, indicating that this effect oc curs via targets other than white adipose tissue. A-ZIP/F-1 mice have marke dly increased liver PPAR gamma mRNA levels, which may be a general property of fatty livers. Rosiglitazone treatment increased the triglyceride conten t of the steatotic Livers of A-ZIP/F-1 and ob/ob mice, but not the "lean" l ivers of fat-transplanted A-ZIP/F-1 mice. In light of this evidence that ro siglitazone acts differently in steatotic livers, the effects of rosiglitaz one, particularly on hepatic triglyceride levels, should be examined in hum ans with hepatic steatosis.