Complex metabolic conditions such as type 2 diabetes and obesity result from the interaction of numerous genetic and environmental factors. While the family of Nme proteins has been connected so far mostly to development, proliferation, or ciliary functions, several lines of evidence from human and experimental studies point to the potential involvement of one of its members, NME7 (non-metastatic cells 7, nucleoside diphosphate kinase 7) in carbohydrate and lipid metabolism. As a complete lack of Nme7 is semilethal in rats, we compared morphometric, metabolic, and transcriptomic profiles of standard diet-fed heterozygous Nme7+/- on male rats vs. their wild-type Nme7+/+ controls. Nme7+/- animals showed increased body weight, adiposity, higher insulin levels together with decreased glucose tolerance. Moreover, they displayed pancreatic islet fibrosis and kidney tubular damage. Despite no signs of overt liver steatosis or dyslipidemia, we found significant changes in the hepatic transcriptome of Nme7+/- male rats with a concerted increase of expression of lipogenic enzymes including Scd1, Fads1, Dhcr7 and a decrease of Cyp7b1 and Nme7. Network analyses suggested possible links between Nme7 and the activation of Srebf1 and Srebf2 upstream regulators. These results further support the implication of NME7 in the pathogenesis of glucose intolerance and adiposity.

• Keywords
• animal models, metabolic syndrome, pancreatic fibrosis,
• MeSH
• Adiposity genetics   MeSH
• Diabetes Mellitus, Type 2 metabolism   MeSH
• Dyslipidemias genetics   MeSH
• Glucose metabolism   MeSH
• Liver metabolism   MeSH
• Rats MeSH
• Lipogenesis genetics   MeSH
• Lipid Metabolism physiology   MeSH
• Nucleoside-Diphosphate Kinase genetics   metabolism   MeSH
• Obesity metabolism   MeSH
• Glucose Intolerance genetics   metabolism   MeSH
• Rats, Sprague-Dawley MeSH
• Transcriptome MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Glucose MeSH
• NME7 protein, human MeSH Browser
• Nucleoside-Diphosphate Kinase MeSH

NME7 (non-metastatic cells 7, nucleoside diphosphate kinase 7) is a member of a gene family with a profound effect on health/disease status. NME7 is an established member of the ciliome and contributes to the regulation of the microtubule-organizing center. We aimed to create a rat model to further investigate the phenotypic consequences of Nme7 gene deletion. The CRISPR/Cas9 nuclease system was used for the generation of Sprague Dawley Nme7 knock-out rats targeting the exon 4 of the Nme7 gene. We found the homozygous Nme7 gene deletion to be semi-lethal, as the majority of SDNme7-/- pups died prior to weaning. The most prominent phenotypes in surviving SDNme7-/- animals were hydrocephalus, situs inversus totalis, postnatal growth retardation, and sterility of both sexes. Thinning of the neocortex was histologically evident at 13.5 day of gestation, dilation of all ventricles was detected at birth, and an external sign of hydrocephalus, i.e., doming of the skull, was usually apparent at 2 weeks of age. Heterozygous SDNme7+/- rats developed normally; we did not detect any symptoms of primary ciliary dyskinesia. The transcriptomic profile of liver and lungs corroborated the histological findings, revealing defects in cell function and viability. In summary, the knock-out of the rat Nme7 gene resulted in a range of conditions consistent with the presentation of primary ciliary dyskinesia, supporting the previously implicated role of the centrosomally located Nme7 gene in ciliogenesis and control of ciliary transport.

• Keywords
• Nme7, cilia, hydrocephalus, infertility, knock-out rat,
• MeSH
• Cilia metabolism   ultrastructure   MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease * MeSH
• Genetic Association Studies MeSH
• Genotype MeSH
• Gene Knockdown Techniques MeSH
• Immunohistochemistry MeSH
• Rats MeSH
• Genes, Lethal * MeSH
• Disease Models, Animal MeSH
• Nucleoside-Diphosphate Kinase deficiency   genetics   metabolism   MeSH
• Ciliary Motility Disorders diagnosis   genetics   MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Gene Expression Regulation MeSH
• X-Ray Microtomography MeSH
• Gene Expression Profiling MeSH
• Transcriptome MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Nucleoside-Diphosphate Kinase MeSH

In mammalian ovaries, follicular atresia occurs periodically and destroys almost all the follicles in the ovary. Follicle-stimulating hormone (FSH) acts as the primary survival factor during follicular atresia by preventing apoptosis in granulosa cells (GCs). Many studies have demonstrated that oxidative stress-induced apoptosis is a main cause of follicular atresia. Reactive oxygen species (ROS)-induced GCs apoptosis is regulated by a variety of signaling pathways involving numerous genes and transcription factors. Therefore, we examined whether FSH inhibits the expression of p53 up-regulated modulator of apoptosis (PUMA) induced by reactive oxygen species (ROS) through phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT) in mouse GCs. In vivo study: thirty-two-mice were randomly assigned to four groups and given FSH. We found that FSH can inhibit the 3-nitropropionic acid (3-NP) induced apoptosis and PUMA expression in mRNA level. Moreover, In vitro experiment, we found that FSH can inhibit the H(2)O(2)-induced apoptosis and PUMA expression in mRNA level. Additionally, we also found that PI3K/AKT inhibitor LY294002 abolished the downregulation of PUMA mRNA by FSH in vitro, In conclusion, FSH inhibit the expression of PUMA induced by ROS through PI3K/AKT pathway in vivo and vitro.

• MeSH
• Apoptosis physiology   MeSH
• Granulosa Cells drug effects   metabolism   MeSH
• Follicle Stimulating Hormone pharmacology   MeSH
• Class I Phosphatidylinositol 3-Kinases metabolism   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred ICR MeSH
• Mice MeSH
• Tumor Suppressor Proteins metabolism   MeSH
• Ovarian Follicle drug effects   metabolism   MeSH
• Primary Cell Culture MeSH
• Apoptosis Regulatory Proteins metabolism   MeSH
• Proto-Oncogene Proteins c-akt metabolism   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Akt1 protein, mouse MeSH Browser
• Follicle Stimulating Hormone MeSH
• Class I Phosphatidylinositol 3-Kinases MeSH
• Tumor Suppressor Proteins MeSH
• Pik3ca protein, mouse MeSH Browser
• Apoptosis Regulatory Proteins MeSH
• Proto-Oncogene Proteins c-akt MeSH
• PUMA protein, mouse MeSH Browser
• Reactive Oxygen Species MeSH