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

Abstract

There is uncertainty about the site(s) of action of the antidiabetic thiazolidinediones (TZDs). These drugs are agonist ligands of the transcription factor PPAR gamma, which is abundant in adipose tissue but is normally present at very low levels in liver and muscle. We have studied the effects of TZDs in A-ZIP/F-1 mice, which lack white adipose tissue. The A-ZIP/F-1 phenotype strikingly resembles that of humans with severe lipoatrophic diabetes, including the lack of fat, marked insulin resistance and hyperglycemia, hyperlipidemia, 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 was effective in lowering circulating triglycerides and increasing whole body fatty acid oxidation in the A-ZIP/F-1 mice, indicating that this effect occurs via targets other than white adipose tissue. A-ZIP/F-1 mice have markedly increased liver PPAR gamma mRNA levels, which may be a general property of fatty livers. Rosiglitazone treatment increased the triglyceride content of the steatotic livers of A-ZIP/F-1 and ob/ob mice, but not the "lean" livers of fat-transplanted A-ZIP/F-1 mice. In light of this evidence that rosiglitazone acts differently in steatotic livers, the effects of rosiglitazone, particularly on hepatic triglyceride levels, should be examined in humans with hepatic steatosis.

Figure 1

Serum chemistries of nonfasted female mice. WT or A-ZIP/F-1 mice, 4–5 weeks old, were treated with a control (filled bars) or rosiglitazone (open bars) diet for 5 weeks. Female ob/ob mice, 6 weeks old, were treated for 2 weeks. Data are mean ± SEM (n = 6). ^AP < 0.05 for differences within each genotype between control and rosiglitazone-treated mice. ^BP < 0.005 for differences within each genotype between control and rosiglitazone-treated mice.

Figure 2

Glucose tolerance testing. Intraperitoneal glucose tolerance tests using 2 mg glucose/kg were performed at approximately 8 hours after lights on, after a 6-hour fast (4). Female WT (circles) and A-ZIP/F-1 (triangles) mice were treated with rosiglitazone (open symbols) or control diets (filled symbols) for 2–4 weeks at the time of testing. Tail vein blood was collected immediately before and at 15, 30, 60, and 120 minutes after glucose injection. Data are the average of two tests per mouse, performed 1 week apart, with six mice per group. A-ZIP/F-1 mice are different from WT at P < 0.05 for all points, with no effect of rosiglitazone treatment.

Figure 3

Rosiglitazone exacerbates hepatic steatosis. Livers from WT (a–d) and A-ZIP/F-1 (e–h) mice, either treated with rosiglitazone (c, d, g, h) or not (a, b, e, f) for 5 weeks, are shown at the same magnification. Hematoxylin and eosin–stained sections of the same livers (original magnification, ×100) show steatosis of the control A-ZIP/F-1 mice, which worsens with rosiglitazone treatment. Liver triglyceride content (i) is shown for control (filled bars) and rosiglitazone-treated (open bars) mice (after 5 weeks of treatment for the A-ZIP/F-1 mice and 2 weeks for the ob/ob mice). Data are mean ± SEM (n = 5–6). ^AP < 0.05 for differences within each genotype between control and rosiglitazone-treated mice. ^BP < 0.005 for differences within each genotype between control and rosiglitazone-treated mice.

Figure 4

Effect of rosiglitazone treatment on fat-transplanted A-ZIP/F-1 mice. WAT (400 mg) was transplanted into A-ZIP/F-1 mice at 5 weeks of age. Serum glucose (a) and insulin (b) were measured weekly (note that the insulin scale is logarithmic). Rosiglitazone (or control) treatment was begun 2 weeks after transplantation. Symbols are filled circles, sham-operated A-ZIP/F-1; open circles, sham-operated, rosiglitazone-treated A-ZIP/F-1; filled triangles, transplanted A-ZIP/F-1; open triangles, transplanted, rosiglitazone-treated A-ZIP/F-1; and filled squares, WT FVB/N. Hepatic weight (c), triglyceride content (d), and PPARγ mRNA (e, f) levels in control (filled bars) or rosiglitazone-treated (open bars) mice at 8 weeks after transplant. WAT transplants increased to 329 ± 59% and 398 ± 87% of initial weight in the control and rosiglitazone-treated groups, respectively. mRNA levels are expressed as a percent of WT levels. Each lane of the Northern blot is from a different mouse. Data are mean ± SEM (n = 5–6).

Figure 5

Liver mRNA levels. Results are for control (filled bars) and rosiglitazone-treated (open bars) mice after 5 weeks of treatment. Data are expressed as a percentage of WT control and are mean ± SEM (n = 4–5). By two-way ANOVA, the genotype effect is significant (P < 0.05) for all except PPARα and CPT1; the treatment effect is significant for SCD1 and AOX, and there is a significant genotype x treatment interaction only for AOX.