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Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes.
We have generated mice that carry a neuron-specific leptin receptor ( LEPR) transgene whose expression is driven by the rat synapsin I promoter synapsin- LEPR B (SYN-LEPR-B). We have also generated mice that are compound hemizygotes for the transgenes SYN-LEPR-B and neuron-specific enolase- LEPR B (NSE-LEPR-B). We observed a degree of correction in db/db mice that are hemizygous (Syn db/db) and homozygous (Syn/Syn db/db) for the SYN-LEPR-B transgene similar to that previously reported for the NSE-LEPR-B transgene. We also show complete correction of the obesity and related phenotypes of db/db mice that are hemizygous for both NSE-LEPR-B and SYN-LEPR-B transgenes (Nse+Syn db/db). Body composition, insulin sensitivity, and cold tolerance were completely normalized in Nse+Syn db/db mice at 12 weeks of age compared with lean controls. In situ hybridization for LEPR B isoform expression in Nse+Syn db/db mice showed robust expression in the energy homeostasis-relevant regions of the hypothalamus. Expression of 3 neuropeptide genes, agouti-related peptide (Agrp), neuropeptide Y (Npy), and proopiomelanocortin ( Pomc), was fully normalized in dual transgenic db/db mice. The 2 transgenes in concert conferred normal fertility to male and female db/db mice. Male mice with partial peripheral deletion of Lepr, induced in the periweaning phase, did not show alterations in body composition or mass. In summary, we show that brain-specific leptin signaling is sufficient to reverse the obesity, diabetes, and infertility of db/db mice.[1]References
- Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. de Luca, C., Kowalski, T.J., Zhang, Y., Elmquist, J.K., Lee, C., Kilimann, M.W., Ludwig, T., Liu, S.M., Chua, S.C. J. Clin. Invest. (2005) [Pubmed]
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