Genetic Obesity and Dietary Sucrose Decrease Hepatic Glucagon and Insulin Receptors in LA/N-Corpulent Rats

Abstract

A catabolic and hypolipemic effect of glucagon has been described in normal animals. We therefore studied the role of glucagon in genetically obese, hyperlipemic rats. Twelve genetically obese hyperlipemic LA/N-cp/cp (corpulent) rats and 12 lean littermates were fed either 54% starch or 54% sucrose for 12 weeks. Plasma glucagon and insulin levels and glucagon and insulin binding to liver membranes were measured. Comparing all corpulent and lean animals regardless of diet, a significant (P < 0.0001) phenotypical effect (cp/cp > lean) was observed in plasma insulin levels (464 ± 54 vs 70.3 ± 7.6 μu/ml, mean ± SEM). Plasma glucagon levels were lower in cp/cp rats (99.6 ± 5.4 vs 127.1 ± 8.6 pg/ml, mean ± SEM). Insulin binding (2.68 vs 16.1%/50 μg protein) and glucagon binding (25.6 vs 47.3%/50 μg protein) were both significantly lower (P < 0.0001) in corpulent rats as compared to their lean littermates. Sucrose feeding had marginal effect on plasma insulin or insulin binding. It, however, decreased glucagon binding in corpulent rats but not in their controls. A significant negative correlation was observed between plasma insulin and insulin binding, while a positive correlation was seen for plasma glucagon and glucagon binding. A significant negative correlation was observed between plasma glucagon and lipogenic enzymes (glucose-6-phosphate dehydrogenase and malic enzyme) in liver and between glucagon binding and these enzymes. We propose that in these genetically obese rats, in addition to hyperinsulinemia, impaired glucagon activity as manifested by decreased glucagon binding to target cells may be an important contributor to the hyperlipemia and obesity. A further decrease in glucagon binding in rats fed sucrose indicates that sucrose, per se, may be an additional contributory factor.