INTERACTIONS BETWEEN LEPTIN AND HYPOTHALAMIC NEUROPEPTIDE-Y NEURONS IN THE CONTROL OF FOOD-INTAKE AND ENERGY HOMEOSTASIS IN THE RAT

Leptin acts on the brain to inhibit feeding, increase thermogenesis, a nd decrease body weight, Neuropeptide Y (NPY)-ergic neurons of the hyp othalamic arcuate nucleus (ARC) that project to the paraventricular nu clei (PVN) and dorsomedial nuclei (DMH) are postulated to control ener gy balance by stimulating feeding and inhibiting thermogenesis, especi ally under conditions of energy deficit. We investigated whether lepti n's short-term effects on energy balance are mediated by inhibition of the NPY neurons, Recombinant murine leptin (11 mu g) injected into th e lateral ventricle of fasted adult Wistar rats inhibited food intake by 20-25% between 2 and 6 h after administration, compared with saline -treated controls (P < 0.05), Uncoupling protein mRNA levels in brown adipose tissue (BAT) rose by 70% (P < 0.01). Leptin treatment signific antly reduced NPY concentrations by 20-50% (P < 0.05) in the ARC, PVN, and DMH and significantly decreased hypothalamic NPY mRNA levels (0.6 1 +/- 0.02 vs, 0.78 +/- 0.03 arbitrary units; P < 0.01), A second stud y examined changes in leptin during 5 days' intracerebroventricular NP Y administration (10 mu g/day), which induced sustained hyperphagia an d excessive weight gain, In NPY-treated rats, leptin mRNA levels in ep ididymal fat were comparable to those in saline-treated controls (0.94 +/- 0.17 vs. 1.0 +/- 0.28 arbitrary units; P > 0.1), but plasma lepti n levels were significantly higher (4.88 +/- 0.66 vs, 2.85 +/- 0.20 ng /ml; P < 0.01), Leptin therefore acts centrally to decrease NPY synthe sis and NPY levels in the ARC-PVN projection; reduced NPY release in t he PVN may mediate leptin's hypophagic and thermogenic actions, Conver sely, NPY-induced obesity results in raised circulating leptin concent rations. Leptin and the NPY-ergic ARC-PVN neurons may interact in a ho meostatic loop to regulate body fat mass and energy balance.