title: Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes.
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.affiliation: Department of Medicine, Division of Preventative Medicine, Columbia University, New York, New York, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: de Luca
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kowalski
authors.forename: Yiying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lee
authors.forename: Manfred W
authors.initials: MW
authors.lastname: Kilimann
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Shun-Mei
authors.initials: SM
authors.lastname: Liu
authors.forename: Streamson C
authors.initials: SC
authors.lastname: Chua
mesh_terms: D054369:Agouti-Related Protein; D000483:Alleles; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D001835:Body Weight; D003080:Cold Temperature; D018076:DNA, Complementary / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000628:therapy*; D005260:Female; D005298:Fertility; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006720:Homozygote; D007031:Hypothalamus / Q000473:pathology; D017403:In Situ Hybridization; D007246:Infertility / Q000235:genetics / Q000628:therapy*; D007247:Infertility, Female / Q000628:therapy; D007248:Infertility, Male / Q000628:therapy; D007328:Insulin / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000628:therapy*; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D016133:Polymerase Chain Reaction; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D011506:Proteins / Q000235:genetics; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics*; D054411:Receptors, Leptin; D015398:Signal Transduction; D016704:Synapsins / Q000235:genetics; D013997:Time Factors; D014018:Tissue Distribution; D019076:Transgenes
chemical_list: D054369:Agouti-Related Protein; D001786:Blood Glucose; D018076:DNA, Complementary; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D010455:Peptides; D020033:Protein Isoforms; D011506:Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D016704:Synapsins; D011333:Pro-Opiomelanocortin; D010751:Phosphopyruvate Hydratase; D005947:Glucose