Overexpressing human lipoprotein lipase in mouse skeletal muscle is associated with insulin resistance

Lipoprotein Lipase (LPL) plays a rate-limiting role in triglyceride-rich Li poprotein metabolism and is expressed in most tissues. Overexpression of LP L in skeletal muscle has been linked with higher plasma glucose levels sugg esting insulin resistance (Jensen et al., Am J Physiol 273:R683-R689, 1997) , The aim of our study was to ascertain whether the overexpression of human LPL in skeletal muscle leads to insulin resistance and to investigate the mechanism. Respiratory quotient measurements in both transgenic (MCKhLPL) a nd nontransgenic mice on a high-carbohydrate diet were conducted and showed a shift in fuel usage in transgenic mice when fasting but not when activel y feeding. An increase in citrate and glucose 6-phosphate levels in fasted MCKhLSL mice further supports this preferential use of Lipids. When challen ged with an intraperitoneal injection of glucose (1 g/kg), MCKhLPL mice had a higher plasma glycemic excursion than nontransgenic mice. No differences in insulin response were observed between the two groups. Further investig ation using hyperinsulinemic-euglycemic clamps revealed insulin resistance in MCKhLPL mice. Despite signs of insulin resistance, there was no associat ed increase in free fatty acids, hypertriglyceridemia, or hyperinsulinemia in MCRhLPL mice. In conclusion, MCKhLPL mice are insulin resistant, presuma bly due to increased delivery of Lipoprotein-derived fatty acids to muscle.