Pioglitazone, a thiazolidinedione (TZD), is widely used as an insulin sensitizer in the treatment of type 2 diabetes. However, body weight gain is frequently observed in TZD-treated patients. Fish oil improves lipid metabolism dysfunction and obesity. In this study, we demonstrated suppression of body weight gain in response to pioglitazone administration by combination therapy of pioglitazone and fish oil in type 2 diabetic KK mice. Male KK mice were fed experimental diets for 8 weeks. In safflower oil (SO), safflower oil/low-dose pioglitazone (S/PL), and safflower oil/high-dose pioglitazone (S/PH) diets, 20% of calories were provided by safflower oil containing 0%, 0.006%, or 0.012% (wt/wt) pioglitazone, respectively. In fish oil (FO), fish oil/low-dose pioglitazone (F/PL), and fish oil/high-dose pioglitazone (F/PH) diets, 20% of calories were provided by a mixture of fish oil and safflower oil. Increased body weight and subcutaneous fat mass were observed in the S/PL and S/PH groups; however, diets containing fish oil were found to ameliorate these changes. Hepatic mRNA levels of lipogenic enzymes were significantly decreased in fish oil-fed groups. These findings demonstrate that the combination of pioglitazone and fish oil decreases subcutaneous fat accumulation, ameliorating pioglitazone-induced body weight gain, through fish oil-mediated inhibition of hepatic de novo lipogenesis.
Keywords: ACC, acetyl-CoA carboxylase; AOX, acyl-CoA oxidase; ATM, adipose tissue macrophage; AUC, area under the curve; Adverse effect; BAT, brown adipose tissue; CPT-1, carnitine palmitoyl transferase 1; CT, computed tomography; DHA, docosahexaenoic acid; ELISA, enzyme-linked immunosorbent assay; EPA, eicosapentaenoic acid; FAS, fatty acid synthase; FFA, free fatty acid; Fish oil; G6pase, glucose-6-phosphatase; GPAT, glycerol-3-phosphate acyltransferase; H&E, hematoxylin and eosin; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; IR, insulin resistance; ITT, insulin tolerance test; Insig-1, insulin-induced gene 1; MCAD, medium-chain acyl-CoA dehydrogenase; MCP-1, monocyte chemoattractant protein-1; OGTT, oral glucose tolerance test; PEPCK, phosphoenolpyruvate carboxykinase; PPARα, peroxisome proliferator-activated receptor alpha; PPARγ, peroxisome proliferator-activated receptor gamma; Pioglitazone; RT-PCR, real-time polymerase chain reaction; SCD-1, stearoyl-CoA desaturase 1; SREBP, sterol regulatory element-binding protein; TLR-4, toll-like receptor-4; TNF-α, tumor necrosis factor-α; TZD, thiazolidinedione; UCP-2, uncoupling protein 2; VLDL, very low-density lipoprotein; WAT, white adipose tissue.