NEURAL SITE OF LEPTIN INFLUENCE ON NEUROPEPTIDE-Y SIGNALING PATHWAYS ALTERING FEEDING AND UNCOUPLING PROTEIN

Inhibition of a signal that produces positive energy balance involving neuropeptide Y (NPY) projection from arcuate nucleus (Arc; site of NP Y synthesis) to paraventricular nucleus (PVN; site of NPY release) is one potential mechanism of leptin action. NPY in the PVN increases fee ding and decreases uncoupling protein (UCP) activity in brown fat, whe reas leptin decreases NPY biosynthesis in the Are, which presumably de creases PVN NPY. It is hypothesized that decreased NPY activity is nec essary for the satiety and thermogenic effects of leptin. To test this , we first determined the effect of leptin on feeding in two paradigms : satiated rats and food-deprived rats. Leptin was effective in decrea sing feeding in the satiated rats but ineffective in the food-deprived rats. Next, we determined that leptin decreases NPY and increases UCP gene expression. Finally, we injected leptin intracerebroventricularl y before specific PVN NPY microinjection. We found that repletion of N PY in PVN by specific NPY microinjection reverses the feeding-inhibito ry and thermogenic effects of centrally administered leptin, the first functional evidence indicating that leptin acts on the Arc-PVN feedin g-regulatory pathway.