neuropeptide-y and Infertility

Neuropeptide Y (NPY) has been implicated in the hypothalamic regulation of reproduction and energy homeostasis. The perikarya located primarily in the arcuate nucleus (ARC) of the hypothalamus constitute a common source of NPY. Projections from these neurons along two distinct pathways, namely, the reproductive axis of the ARC--median eminence--medial preoptic area and the orexigenic axis of the ARC--paraventricular nucleus and neighboring regions, participate in regulation of these two neuroendocrine functions. Additionally, the NPY neuronal system within the basal hypothalamus is morphologically and functionally linked with galanin and the opioid networks which also play roles in the control of reproduction and ingestive behavior. Recent experimental evidence indicates that genetic, hormonal, and environmental factors that cause nutritional imbalance and metabolic disturbances, along with depressed pituitary gonadal function, produce alterations in the synthesis, storage, and release of NPY and in other connected peptidergic systems in the hypothalamus. The current findings summarized in this review support our concept that NPY may-be one of the essential messenger molecules that serve as a communication bridge between the neural processes that regulate reproduction and those that maintain energy homeostasis. Modification in information flow within this peptidergic network due to nutritional imbalance may adversely impact hypothalamo-pituitary-gonadal function.

Topics: Animal Nutritional Physiological Phenomena; Animals; Female; Galanin; Humans; Hypothalamus; Infertility; Neuropeptide Y; Nutritional Physiological Phenomena; Pregnancy; Receptors, Opioid; Reproduction

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

Secretion of leptin from adipocytes communicates body energy status to the brain by activating the leptin receptor long form (LRb). LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes. Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin action. To investigate the contribution of STAT3 signalling to leptin action in vivo, we replaced the gene encoding the leptin receptor (lepr) in mice with an allele coding for a replacement of Tyr 1138 in LRb with a serine residue (lepr(S1138)) that specifically disrupts the LRb-STAT3 signal. Here we show that, like db/db mice, lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short and diabetic, s/s mice are fertile, long and less hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. LRb-STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis.

Topics: Alleles; alpha-MSH; Animals; Blood Glucose; Body Weight; Cell Line; Diabetes Mellitus; DNA-Binding Proteins; Energy Metabolism; Estrous Cycle; Female; Homeostasis; Humans; Infertility; Leptin; Male; Mice; Neuropeptide Y; Obesity; Phenotype; Receptors, Cell Surface; Receptors, Leptin; Reproduction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Trans-Activators

Topics: Animals; Embryo Implantation; Female; Gonadotropins, Pituitary; Humans; Infertility; Male; Neuropeptide Y; Ovary; Reproduction; Testis; Uterus