RGD Reference Report - Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. - Rat Genome Database

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Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes.

Authors: De Luca, C  Kowalski, TJ  Zhang, Y  Elmquist, JK  Lee, C  Kilimann, MW  Ludwig, T  Liu, SM  Chua SC, JR 
Citation: de Luca C, etal., J Clin Invest. 2005 Dec;115(12):3484-93. Epub 2005 Nov 10.
RGD ID: 10412018
Pubmed: PMID:16284652   (View Abstract at PubMed)
PMCID: PMC1280964   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI24059   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
infertility treatmentISOLepr (Mus musculus)10412018; 10412018 RGD 
infertility treatmentIMP 10412018 RGD 
obesity treatmentISOLepr (Mus musculus)10412018; 10412018 RGD 
obesity treatmentIMP 10412018 RGD 
type 2 diabetes mellitus treatmentISOLepr (Mus musculus)10412018; 10412018 RGD 
type 2 diabetes mellitus treatmentIMP 10412018 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Lepr  (leptin receptor)

Genes (Mus musculus)
Lepr  (leptin receptor)

Genes (Homo sapiens)
LEPR  (leptin receptor)

Additional Information