neuropeptide-y and Infertility--Male

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.

Topics: Agouti-Related Protein; Alleles; Animals; Blood Glucose; Body Composition; Body Weight; Cold Temperature; Diabetes Mellitus; DNA, Complementary; Female; Fertility; Gene Expression Regulation; Genetic Therapy; Genotype; Glucose; Homeostasis; Homozygote; Hypothalamus; In Situ Hybridization; Infertility; Infertility, Female; Infertility, Male; Insulin; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Transgenic; Neurons; Neuropeptide Y; Obesity; Peptides; Phenotype; Phosphopyruvate Hydratase; Polymerase Chain Reaction; Pro-Opiomelanocortin; Promoter Regions, Genetic; Protein Isoforms; Proteins; Rats; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Synapsins; Time Factors; Tissue Distribution; Transgenes