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

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.

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3484-3493
Number of pages10
JournalJournal of Clinical Investigation
Volume115
Issue number12
DOIs
StatePublished - Dec 2005

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Leptin Receptors
Transgenes
Infertility
Obesity
Synapsins
Neurons
Phosphopyruvate Hydratase
Body Composition
Hemizygote
Pro-Opiomelanocortin
Neuropeptide Y
Leptin
Neuropeptides
Hypothalamus
In Situ Hybridization
Fertility
Insulin Resistance
Protein Isoforms
Homeostasis
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

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Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. / De Luca, Carl; Kowalski, Timothy J.; Zhang, Yiying; Elmquist, Joel K.; Lee, Charlotte; Kilimann, Manfred W.; Ludwig, Thomas; Liu, Shun Mei; Chua, Jr., Streamson C.

In: Journal of Clinical Investigation, Vol. 115, No. 12, 12.2005, p. 3484-3493.

Research output: Contribution to journalArticle

De Luca, C, Kowalski, TJ, Zhang, Y, Elmquist, JK, Lee, C, Kilimann, MW, Ludwig, T, Liu, SM & Chua, Jr., SC 2005, 'Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes', Journal of Clinical Investigation, vol. 115, no. 12, pp. 3484-3493. https://doi.org/10.1172/JCI24059
De Luca, Carl ; Kowalski, Timothy J. ; Zhang, Yiying ; Elmquist, Joel K. ; Lee, Charlotte ; Kilimann, Manfred W. ; Ludwig, Thomas ; Liu, Shun Mei ; Chua, Jr., Streamson C. / Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. In: Journal of Clinical Investigation. 2005 ; Vol. 115, No. 12. pp. 3484-3493.
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AU - De Luca, Carl

AU - Kowalski, Timothy J.

AU - Zhang, Yiying

AU - Elmquist, Joel K.

AU - Lee, Charlotte

AU - Kilimann, Manfred W.

AU - Ludwig, Thomas

AU - Liu, Shun Mei

AU - Chua, Jr., Streamson C.

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