This study was designed to examine the effect of a high-fat (primarily saturated), refined-carbohydrate (sucrose) diet (HFS), which is known to induce obesity and hyperlipidemia, on adipose tissue and skeletal muscle lipoprotein lipase (LPL) and very-low density lipoprotein receptor (VLDL-R) protein expressions. Female Fischer rats were placed on either a HFS or a low-fat, complex-carbohydrate (LFCC) diet for 22 months beginning at 2 months of age. After 20 months, a subgroup of the HFS rats were switched to the LFCC diet for 2 months (HFS/LFCC). Body weight, feed efficiency, plasma total cholesterol, VLDL-C, low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) concentrations and LDL-C to high-density lipoprotein cholesterol ratio were all significantly raised by the HFS diet and improved by conversion to the LFCC diet. Adipose tissue heparin-releasable, extractable and total LPL activity expressed per cell were significantly increased in the HFS-fed group. However, LPL protein abundance normalized against total cellular protein was unchanged in the HFS group. This observation is consistent with the presence of adipose tissue hypertrophy. Skeletal muscle LPL protein abundance and heparin-releasable activity were reduced by the HFS diet and improved after switching to the LFCC diet. Both adipose tissue and skeletal muscle VLDL-R protein levels were significantly reduced by the HFS diet and increased after conversion to the LFCC diet. We conclude that an HFS diet induces changes in LPL and VLDL-R in a manner which favors shunting of dietary fat from skeletal muscle to adipose tissue and decreases TG-rich lipoprotein clearance contributing to increased plasma lipids and obesity. Conversion to a LFCC diet can ameliorate the dyslipidemia and tissue changes induced by long-term HFS diet consumption.