PREVENTION OF DIET-INDUCED OBESITY IN TRANSGENIC MICE OVEREXPRESSING SKELETAL-MUSCLE LIPOPROTEIN-LIPASE

Transgenic (Tg) FVB/N mice were produced that overexpress human lipopr otein lipase (LPL) in skeletal muscle using the muscle creatine kinase promoter and enhancers. It was hypothesized that, by overexpressing L PL in muscle, high fat feeding-induced obesity would be prevented by d iverting lipoprotein-derived triglyceride fatty acids away from storag e in adipose tissue to oxidation in muscle. Mice were examined both at 6 wk of age before high fat (HF) feeding and at 19 wk of age after 13 wk of HF (46.1% fat) or high carbohydrate (HC) feeding (11.5% fat). A t 6 wk in heterozygous Tg mice, LPL was increased 11-fold in white mus cle and 2.5-fold in red muscle, but not in cardiac muscle or spleen, b rain, lung, kidney, or adipose tissue. Plasma triglycerides (mg/dl) we re lower in Tg mice (87 +/- 7 vs. 117 +/- 7, P < 0.0001), and glucose increased (201 +/- 9 vs. 167 +/- 8 mg/dl, P = 0.029). There were no di fferences in body weight between Tg and nontransgenic (nTg) mice; howe ver, carcass lipid content (%body wt) was significantly decreased in m ale Tg mice at 6 wk (7.5 +/- 1.0 vs. 9.0 +/- 1.0%, P = 0.035). Body co mposition was not different in female Tg mice at 6 wk. Overall, when T g mice were fed either a HC or HF diet for 13 wk, plasma triglycerides (P < 0.001) and free fatty acids (P < 0.001) were decreased, whereas plasma glucose (P = 0.01) and insulin (P = 0.05) were increased compar ed with nTg mice. HF feeding increased carcass lipid content twofold i n both male (10.3 +/- 1.1 vs. 21.4 +/- 2.6%, HC vs. HF, P < 0.001) and female nTg mice (6.7 +/- 0.9 vs. 12.9 +/- 1.8%, P = 0.01). However, t he targeted overexpression of LPL in skeletal muscle prevented HF diet -induced lipid accumulation in both Tg male (10.2 +/- 0.7 vs. 13.5 +/- 2.2%, HC vs. HF, P = NS) and female Tg mice (6.8 +/- 0.6 vs. 10.1 +/- 1.4%, P = NS). The potential to increase LPL activity in muscle by ge ne or drug delivery may prove to be an effective tool in preventing an d/or treating obesity in humans.