Selective deletion of leptin receptor in neurons leads to obesity
Paul Cohen, … , Peter Mombaerts, Jeffrey M. Friedman
Paul Cohen, … , Peter Mombaerts, Jeffrey M. Friedman
Published October 15, 2001
Citation Information: J Clin Invest. 2001;108(8):1113-1121. https://doi.org/10.1172/JCI13914.
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Article

Selective deletion of leptin receptor in neurons leads to obesity

Abstract

Animals with mutations in the leptin receptor (ObR) exhibit an obese phenotype 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 resolved. To address this, we generated mice with neuron-specific (ObRSynIKO) and hepatocyte-specific (ObRAlbKO) disruption of ObR. Among the ObRSynIKO mice, the extent of obesity was negatively correlated with the level of ObR in hypothalamus and those animals with the lowest levels of ObR exhibited an obese phenotype. The obese mice with low levels of hypothalamic ObR also show elevated plasma levels of leptin, glucose, insulin, and corticosterone. The hypothalamic levels of agouti-related protein and neuropeptide Y RNA are increased in these mice. These data indicate that leptin has direct effects on neurons and that a significant proportion, or perhaps the majority, 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 also characterized ObRAlbKO mice. These mice weigh the same as controls and have no alterations in body composition. Moreover, while db/db mice and ObRSynIKO mice have enlarged fatty livers, ObRAlbKO mice do not. In summary, these data suggest that the brain is a direct target for the weight-reducing and neuroendocrine effects of leptin and that the liver abnormalities of db/db mice are secondary to defective leptin signaling in the brain.

Authors

Paul Cohen, Connie Zhao, Xiaoli Cai, Jason M. Montez, S. Christy Rohani, Paul Feinstein, Peter Mombaerts, Jeffrey M. Friedman

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Obesity in a subset of ObRSynIKO mice. Significant obesity was evident i...
Obesity in a subset of ObRSynIKO mice. Significant obesity was evident in those ObRSynIKO mice that had 15% or less ObR RNA in the hypothalamus than did wild-type mice. (a) Weight curves of male and female ObRSynIKO mice (filled squares), heterozygote littermates (open squares), and ObR-null mice (filled triangles). Mice were weighed weekly from 5 weeks of age. Data represent the mean ± SEM of four male and two female ObRSynIKO mice, seven male and nine female heterozygote littermates, and six male and five female ObR-null mice. For both sexes, ObRSynIKO versus heterozygotes, P < 0.05 at all ages; ObRSynIKO versus ObR-null, P < 0.05 at all ages. (b) Expression levels of AGRP, NPY, POMC, and CART were determined by Taqman and are expressed as normalized to cyclophilin. Levels were measured in ObRSynIKO, heterozygotes (HET), and ObR-nulls. (n = 5 for heterozygotes, n = 6 for knockouts, and n = 3 for null mice.)