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Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes
Carl de Luca, … , Shun-Mei Liu, Streamson C. Chua Jr.
Carl de Luca, … , Shun-Mei Liu, Streamson C. Chua Jr.
Published December 1, 2005
Citation Information: J Clin Invest. 2005;115(12):3484-3493. https://doi.org/10.1172/JCI24059.
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Research Article Metabolism

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

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Abstract

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.

Authors

Carl de Luca, Timothy J. Kowalski, Yiying Zhang, Joel K. Elmquist, Charlotte Lee, Manfred W. Kilimann, Thomas Ludwig, Shun-Mei Liu, Streamson C. Chua Jr.

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Figure 9

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Deletion of peripheral signaling LEPR has no effect on adiposity. (A) Re...
Deletion of peripheral signaling LEPR has no effect on adiposity. (A) Representative results of PCR-based genotyping of the Lepr locus in the tissues of male Cre+Tam mice. Four-month-old male Cre+Tam mice and nonCre+Tam controls were sacrificed 3 months after Tam treatment. PCR-based DNA analysis was used to determine the extent of the deletion of exon 17 (Lepr-δ17) in the brain (Bra), hypothalamus, liver, kidney (Kid), pancreas, small intestine (Int), skeletal muscle, inguinal fat (Ing), perigonadal fat (PG), retroperitoneal fat (Ret), brown adipose tissue, and tail. Tail DNA of a Leprflox/δ17 mouse was used as a control (Ctrl). (B) Body compositions of 4-month-old male Cre+Tam mice (n = 7) and their nonCre+Tam controls (n = 5) were determined using DEXA 3 months after Tam treatment.

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