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 2

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Cre-mediated recombination specifically in the brain of ObRSynIKO mice. ...
Cre-mediated recombination specifically in the brain of ObRSynIKO mice. (a) The breeding strategy that was used to generate ObRSynIKO mice and littermate controls. ObRAlbKO mice (described below) were generated using the same strategy. (b) Genomic DNA was prepared from several tissues from ObRflox/+, SynI-Cre(+) mice and were PCR-amplified using primers flanking the first coding exon of ObR. The locations of the primers are shown on the schematic below the gel. In tissues expressing the Cre recombinase, exon 1 is excised and a single loxP site remains, generating an ObRΔ allele. While primers 1 and 3 can amplify a product from the ObRΔ allele, in the ObRflox or ObR+ (wild-type) DNA, the primers are separated by a distance too great for amplification to occur. As a control, primers 1 and 2 were used to amplify both the ObRflox allele and the ObR+ alleles from all tissues. The ObR+ allele produces a slightly smaller product due to the absence of loxP sequences.