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Complete rescue of ...
Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes
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de Luca, Carl (author)
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Kowalski, Timothy J (author)
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Zhang, Yiying (author)
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Elmquist, Joel K (author)
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Lee, Charlotte (author)
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- Kilimann, Manfred W (author)
- Uppsala universitet,Institutionen för neurovetenskap
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Ludwig, Thomas (author)
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Liu, Shun-Mei (author)
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Chua, Streamson C (author)
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(creator_code:org_t)
- 2005
- 2005
- English.
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In: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 115:12, s. 3484-3493
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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.
Keyword
- MEDICINE
- MEDICIN
Publication and Content Type
- ref (subject category)
- art (subject category)
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