Reduced body weight is a common effect of gene knockout in mice

<p>Abstract</p> <p>Background</p> <p>During a search for obesity candidate genes in a small region of the mouse genome, we noticed that many genes when knocked out influence body weight. To determine whether this was a general feature of gene knockout or a chance occurrence, we surveyed the Jackson Laboratory Mouse Genome Database for knockout mouse strains and their phenotypes. Body weights were not available for all strains so we also obtained body weight information by contacting a random sample of investigators responsible for a knockout strain.</p> <p>Results</p> <p>We classified each knockout mouse strain as (1) lighter and smaller, (2) larger and heavier, or (3) the same weight, relative to control mice. We excluded knockout strains that died early in life, even though this type of lethality is often associated with a small embryo or reduced body size. Based on a dataset of 1,977 knockout strains, we found that that 31% of viable knockout mouse strains weighed less and an additional 3% weighed more than did controls.</p> <p>Conclusion</p> <p>Body weight is potentially a latent variable in about a third of experiments that use knockout mice and should be considered in interpreting experimental outcomes, e.g., in studies of hypertension, drug and hormone metabolism, organ development, cell proliferation and apoptosis, digestion, heart rate, or atherosclerosis. If we assume that the knockout genes we surveyed are representative then upward of 6,000 genes are predicted to influence the size of a mouse. Body weight is highly heritable, and numerous quantitative trait loci have been mapped in mice, but "multigenic" is an insufficient term for the thousands of loci that could contribute to this complex trait.</p

Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis

Peer reviewedPublisher PD

Is paternal age associated with transfer day, developmental stage, morphology, and initial hCG-rise of the competent blastocyst leading to live birth?:A multicenter cohort study

In this study we investigated whether age of men undergoing assisted reproductive technology (ART) treatment was associated with day of transfer, stage, morphology, and initial hCG-rise of the competent blastocyst leading to a live birth? The design was a multicenter historical cohort study based on exposure (age) and outcome data (blastocyst stage and morphology and initial hCG-rise) from men whose partner underwent single blastocyst transfer resulting in singleton pregnancy/birth. The ART treatments were carried out at sixteen private and university-based public fertility clinics. We included 7246 men and women, who between 2014 and 2018 underwent controlled ovarian stimulation (COS) or Frozen-thawed Embryo Transfer (FET) with a single blastocyst transfer resulting in singleton pregnancy were identified. 4842 men with a partner giving birth were included, by linking data to the Danish Medical Birth Registry. We showed that the adjusted association between paternal age and transfer day in COS treatments was OR 1.06, 95% CI (1.00;1.13). Meaning that for every increase of one year, men had a 6% increased probability that the competent blastocyst was transferred on day 6 compared to day 5. Further we showed that the mean difference in hCG values when comparing paternal age group 30–34, 35–39 and 40–45 with the age group 25–29 in those receiving COS treatment, all showed significantly lower adjusted values for older men. In conclusion we hypothesize that the later transfer (day 6) in female partners of older men may be due to longer time spent by the oocyte to repair fragmented DNA of the sperm cells, which should be a focus of future research in men

Three options for citation tracking: Google Scholar, Scopus and Web of Science

BACKGROUND: Researchers turn to citation tracking to find the most influential articles for a particular topic and to see how often their own published papers are cited. For years researchers looking for this type of information had only one resource to consult: the Web of Science from Thomson Scientific. In 2004 two competitors emerged – Scopus from Elsevier and Google Scholar from Google. The research reported here uses citation analysis in an observational study examining these three databases; comparing citation counts for articles from two disciplines (oncology and condensed matter physics) and two years (1993 and 2003) to test the hypothesis that the different scholarly publication coverage provided by the three search tools will lead to different citation counts from each. METHODS: Eleven journal titles with varying impact factors were selected from each discipline (oncology and condensed matter physics) using the Journal Citation Reports (JCR). All articles published in the selected titles were retrieved for the years 1993 and 2003, and a stratified random sample of articles was chosen, resulting in four sets of articles. During the week of November 7–12, 2005, the citation counts for each research article were extracted from the three sources. The actual citing references for a subset of the articles published in 2003 were also gathered from each of the three sources. RESULTS: For oncology 1993 Web of Science returned the highest average number of citations, 45.3. Scopus returned the highest average number of citations (8.9) for oncology 2003. Web of Science returned the highest number of citations for condensed matter physics 1993 and 2003 (22.5 and 3.9 respectively). The data showed a significant difference in the mean citation rates between all pairs of resources except between Google Scholar and Scopus for condensed matter physics 2003. For articles published in 2003 Google Scholar returned the largest amount of unique citing material for oncology and Web of Science returned the most for condensed matter physics. CONCLUSION: This study did not identify any one of these three resources as the answer to all citation tracking needs. Scopus showed strength in providing citing literature for current (2003) oncology articles, while Web of Science produced more citing material for 2003 and 1993 condensed matter physics, and 1993 oncology articles. All three tools returned some unique material. Our data indicate that the question of which tool provides the most complete set of citing literature may depend on the subject and publication year of a given article

Leptin Resistance in Vagal Afferent Neurons Inhibits Cholecystokinin Signaling and Satiation in Diet Induced Obese Rats

Background and Aims: The gastrointestinal hormone cholecystokinin (CCK) plays an important role in regulating meal size and duration by activating CCK1 receptors on vagal afferent neurons (VAN). Leptin enhances CCK signaling in VAN via an early growth response 1 (EGR1) dependent pathway thereby increasing their sensitivity to CCK. In response to a chronic ingestion of a high fat diet, VAN develop leptin resistance and the satiating effects of CCK are reduced. We tested the hypothesis that leptin resistance in VAN is responsible for reducing CCK signaling and satiation. Results: Lean Zucker rats sensitive to leptin signaling, significantly reduced their food intake following administration of CCK8S (0.22 nmol/kg, i.p.), while obese Zucker rats, insensitive to leptin, did not. CCK signaling in VAN of obese Zucker rats was reduced, preventing CCK-induced up-regulation of Y2 receptor and down-regulation of melanin concentrating hormone 1 receptor (MCH1R) and cannabinoid receptor (CB1). In VAN from diet-induced obese (DIO) Sprague Dawley rats, previously shown to become leptin resistant, we demonstrated that the reduction in EGR1 expression resulted in decreased sensitivity of VAN to CCK and reduced CCK-induced inhibition of food intake. The lowered sensitivity of VAN to CCK in DIO rats resulted in a decrease in Y2 expression and increased CB1 and MCH1R expression. These effects coincided with the onset of hyperphagia in DIO rats. Conclusions: Leptin signaling in VAN is required for appropriate CCK signaling and satiation. In response to high fat feeding

Role of the IRS-1 and/or -2 in the pathogenesis of insulin resistance in Dahl salt-sensitive (S) rats

Insulin resistance is a common finding in hypertensive humans and animal models. The Dahl salt-sensitive (S) rat is an ideal model of genetically predetermined insulin resistance and salt-sensitive hypertension. Along the insulin signaling pathway, the insulin receptor substrates 1 and 2 (IRS-1 and -2) are important mediators of insulin signaling. IRS-1 and/or IRS-2 genetic variant(s) and/or enhanced serine phosphorylation correlate with insulin resistance. The present commentary was designed to highlight the significance of IRS-1 and/or -2 in the pathogenesis of insulin resistance. An emphasis will be given to the putative role of IRS-1 and/or -2 genetic variant(s) and serine phosphorylation in precipitating insulin resistance

Inducible liver-specific knockdown of protein tyrosine phosphatase 1B improves glucose and lipid homeostasis in adult mice.

AIMS/HYPOTHESIS Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signalling. Hepatic PTP1B deficiency, using the Alb-Cre promoter to drive Ptp1b deletion from birth in mice, improves glucose homeostasis, insulin sensitivity and lipid metabolism. The aim of this study was to investigate the therapeutic potential of decreasing liver PTP1B levels in obese and insulin-resistant adult mice. METHODS Inducible Ptp1b liver-specific knockout mice were generated using SA-Cre-ER(T2) mice crossed with Ptp1b floxed (Ptp1b(fl/fl)) mice. Mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity and insulin resistance. Tamoxifen was administered in the HFD to induce liver-specific deletion of Ptp1b (SA-Ptp1b(-/-) mice). Body weight, glucose homeostasis, lipid homeostasis, serum adipokines, insulin signalling and endoplasmic reticulum (ER) stress were examined. RESULTS Despite no significant change in body weight relative to HFD-fed Ptp1b(fl/fl) control mice, HFD-fed SA-Ptp1b(-/-) mice exhibited a reversal of glucose intolerance as determined by improved glucose and pyruvate tolerance tests, decreased fed and fasting blood glucose and insulin levels, lower HOMA of insulin resistance, circulating leptin, serum and liver triacylglycerols, serum NEFA and decreased HFD-induced ER stress. This was associated with decreased glycogen synthase, eukaryotic translation initiation factor-2α kinase 3, eukaryotic initiation factor 2α and c-Jun NH2-terminal kinase 2 phosphorylation, and decreased expression of Pepck. CONCLUSIONS/INTERPRETATION Inducible liver-specific PTP1B knockdown reverses glucose intolerance and improves lipid homeostasis in HFD-fed obese and insulin-resistant adult mice. This suggests that knockdown of liver PTP1B in individuals who are already obese/insulin resistant may have relatively rapid, beneficial therapeutic effects