Short-term pharmacological
melanocortin activation deters diet-induced
obesity (DIO) effectively in rodents. However, whether central
pro-opiomelanocortin (
POMC) gene transfer targeted to the hypothalamus or hindbrain nucleus of the solitary track (NTS) can combat chronic dietary
obesity has not been investigated. Four-weeks-old Sprague-Dawley rats were fed a high fat diet for 5 months, and then injected with either the
POMC or control vector into the hypothalamus or NTS, and
body weight and food intake recorded for 68 days.
Insulin sensitivity,
glucose metabolism and adrenal indicators of central sympathetic activation were measured, and voluntary wheel running (WR) assessed. Whereas the NTS
POMC-treatment decreased cumulative food consumption and caused a sustained
weight reduction over 68 days, the hypothalamic
POMC-treatment did not alter cumulative food intake and produced
weight loss only in the first 25 days. At death, only the NTS-
POMC rats had a significant decrease in fat mass. They also displayed enhanced
glucose tolerance, lowered fasting
insulin and increased QUICK value, and elevated adrenal indicators of central sympathetic activation. Moreover, the NTS-
POMC animals exhibited a near 20% increase in distance ran relative to the respective controls, but the
ARC-
POMC rats did not. In conclusion,
POMC gene transfer to the NTS caused modest
anorexia, persistent
weight loss, improved
insulin sensitivity, and increased propensity for WR in DIO rats. These metabolic improvements may involve stimulation of energy expenditure via centrally regulated sympathetic outflow. The similar
POMC treatment in the hypothalamus had minimal long-term physiological or metabolic impact. Thus,
melanocortin activation in the brainstem NTS region effectively ameliorates chronic dietary
obesity whilst that in the hypothalamus fails to do so.