Pioglitazone Induces In Vivo Adipocyte Differentiation in the Obese Zucker fa/fa Rat

Abstract

Thiazolidinediones are potent antidiabetic compounds, in both animal and human models, which act by enhancing peripheral sensitivity to insulin. Thiazolidinediones are high-affinity ligands for peroxisome proliferator-activated receptor-gamma, a key factor for adipocyte differentiation, and they are efficient promoters of adipocyte differentiation in vitro. Thus, it could be questioned whether a thiazolidinedione therapy aimed at improving insulin sensitivity would promote the recruitment of new adipocytes in vivo. To address this problem, we have studied the in vivo effect of pioglitazone on glucose metabolism and gene expression in the adipose tissue of an animal model of obesity with insulin resistance, the obese Zucker (fa/fa) rat. Pioglitazone markedly improves insulin action in the obese Zucker (fa/fa) rat, but doubles its weight gain after 4 weeks of treatment. The drug induces a large increase of glucose utilization in adipose tissue, where it stimulates the expression of genes involved in lipid metabolism such as the insulin-responsive GLUT, fatty acid synthase, and phosphoenolpyruvate carboxykinase genes, but decreases the expression of the ob gene. These changes are related to both an enhanced adipocyte differentiation, as shown by the large increase in the number of small adipocytes in the retroperitoneal fat pad, and a direct effect of pioglitazone on specific gene expression (phosphoenolpyruvate carboxykinase and ob genes) in mature adipocytes.

Effects of Dietary Thiazolidinedione Supplementation on Growth Performance, Intramuscular Fat and Related Genes mRNA Abundance in the Longissimus Dorsi Muscle of Finishing Pigs

“…Moreover, it has been reported the expression of FABP3 was positively correlated with the IMF content (Cho et al, 2011), thus the increased IMF levels in the TZD group could be associated with the up-regulated expression of FABP3. There was no difference in the mRNA abundance of GLUT4 between the control and TZD groups, which was inconsistent with the findings of other researches (Hallakou et al, 1997; Miyazaki et al, 2002). It suggested TZD had no effect on glucose utilization when it was supplemented for healthy animals.…”

“…Moreover, TZD supplementation increased the mRNA abundance of FABP3 mRNA by 65.12% above that of the control group, indicating an up-regulated transport and accretion of fatty acids in the muscle of TZD-fed animals. This is consistent with the findings of Hallakou (1997) showing that a TZD treatment of the obese Zucker rat induced a marked increase in weight gain, and stimulated the expression of genes necessary for lipid metabolism. Moreover, it has been reported the expression of FABP3 was positively correlated with the IMF content (Cho et al, 2011), thus the increased IMF levels in the TZD group could be associated with the up-regulated expression of FABP3.…”

Rosiglitazone-Induced Mitochondrial Biogenesis in White Adipose Tissue Is Independent of Peroxisome Proliferator-Activated Receptor γ Coactivator-1α

“…The capacity of TZDs to ameliorate insulin resistance is typically attributed to their ability to activate PPARγ and promote adipogenesis [24], [25]. By enhancing the formation of new adipocytes, TZDs are thought to drive triacylglycerol storage in adipose tissues, reduce circulating lipid levels and prevent lipid accumulation and toxicity in other insulin-sensitive tissues [1].…”

Effects of pioglitazone on nonalcoholic steatohepatitis in a patient with anorexia nervosa: A case report

“…Furthermore, a previous study showed that pioglitazone was also effective for alcoholic steatohepatitis in rats without altering insulin sensitivity (20). Pioglitazone promotes the differentiation of pre-adipocytes into adipocytes (21–23) and may result in the redistribution of triglycerides from the liver into proliferating adipocytes. Pioglitazone is generally known to cause weight gain as an adverse effect, which is supported in this case as the patient gained 8 kg of body weight.…”