Chronic Ventromedial Hypothalamic Infusion of Norepinephrine and Serotonin Promotes Insulin Resistance and Glucose Intolerance

Abstract

The ventromedial hypothalamus (VMH) is involved in the regulation of peripheral metabolism. We and others have shown that activities, or extracellular metabolites of norepinephrine (NE) and serotonin (5-HT) are elevated in the VMH of both genetically and seasonally insulin-resistant and glucose-intolerant animals. This study examined whether chronic increases in VMH NE and 5-HT concentration of normal animals might lead to insulin-resistant and glucose-intolerant conditions in hamsters. Euinsulinemic, glucose-tolerant hamsters were infused continuously for 5 weeks into the right VMH with either vehicle, NE (5 or 25 nmol/h), 5-HT (2.5 nmol/h), or NE (5 or 25 nmol/h) plus 5-HT (2.5 nmol/h) through osmotic minipumps. Compared to vehicle, NE (25 nmol/h) significantly increased the glucose total area under the curve (TAUC) by 32% during glucose tolerance tests (GTT) conducted after 5 weeks' infusion. 5-HT alone significantly increased the GTT insulin TAUC (131%) and basal plasma insulin level (116%) but not glucose TAUC. NE (5 nmol/h) plus 5-HT infusion significantly increased insulin TAUC (129%) and basal plasma insulin (120%), whereas NE (25 nmol/h) plus 5-HT infusion significantly increased both the GTT glucose and insulin TAUC (43 and 113%, respectively), as well as basal plasma insulin level (158%), relative to vehicle infusion. Our findings demonstrate for the first time the differential and, more importantly, interactive effects of increased VMH NE and 5-HT in producing hyperinsulinemia, insulin resistance and glucose intolerance.