Selective deletion of leptin receptor in neurons leads to obesity

Animals with mutations in the leptin receptor (ObR) exhibit an obese phenot ype that is indistinguishable from that of leptin deficient ob/ob mice. ObR is expressed in many tissues, including brain, and the relative importance of leptin's effects on central versus peripheral sites has not been resolv ed. To address this, we generated mice with neuron-specific (ObR(SynI)KO) a nd hepatocyte-specific (ObR(Alb)KO) disruption of ObR. Among the ObR(SynI)K O mice, the extent of obesity was negatively correlated with the level of O bR in hypothalamus and those animals with the lowest levels of ObR exhibite d an obese phenotype. The obese mice with low levels of hypothalamic ObR al so show elevated plasma levels of leptin, glucose, insulin, and corticoster one. The hypothalamic levels of agouti-related protein and neuropeptide Y R NA are increased in these mice. These data indicate that leptin has direct effects on neurons and that a significant proportion, or perhaps the majori ty, of its weight-reducing effects are the result of its actions on brain. To explore possible direct effects of leptin on a peripheral tissue, we als o characterized ObR(Alb)KO mice. These mice weigh the same as controls and have no alterations in body composition. Moreover, while db/db mice and ObR (SynI)KO mice have enlarged fatty livers, ObR(Alb)KO mice do not. In summar y, these data suggest that the brain is a direct target for the weight-redu cing and neuroendocrine effects of leptin and that the liver abnormalities of db/db mice are secondary to defective leptin signaling in the brain.