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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Figure 5

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Normal body weight and liver phenotype in ObRAlbKO mice. (a) Schematic o...
Normal body weight and liver phenotype in ObRAlbKO mice. (a) Schematic of Albumin-Cre transgene. (b) Genomic DNA was prepared from several tissues from ObRflox/+, Alb-Cre(+) mice and was PCR-amplified using primers flanking the first coding exon of ObR as described in Figure 2b. (c) Weight curves of male and female ObRAlbKO mice (filled squares) and heterozygote littermates (open squares). Mice were weighed weekly from 5 weeks of age. Data represent the mean ± SEM of 9 male and 11 female ObRAlbKO mice and 23 male and 23 female heterozygote littermates. For both sexes, ObRAlbKO versus heterozygotes, P values were not significant at all ages. (d) Photographs of freshly dissected livers from representative mice with the given genotypes. (e) Liver triglycerides (milligrams of triglyceride per grams of liver) were determined for ObRAlbKO mice with less than 30% of wild-type ObR RNA and heterozygote controls. Data represent the mean ± SEM of six male and five female ObRAlbKO mice, five male and five female heterozygote controls, and six male and three female ObR-null mice. For both sexes, P < 0.05 for ObRAlbKO and heterozygotes relative to ObR null.