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Schlafen 3 knockout mice display gender-specific differences in weight gain, food efficiency, and expression of markers of intestinal epithelial differentiation, metabolism, and immune cell function.

ABSTRACT: Self-renewal and differentiation are essential for intestinal epithelium absorptive functioning and adaptation to pathological states such as short gut syndrome, ulcers, and inflammatory bowel disease. The rodent Slfn3 and its human analog Slfn12 are critical in regulating intestinal epithelial differentiation. We sought to characterize intestinal function in Slfn3 knockout (KO) mice. Male and female pair-fed Slfn3KO mice gained less weight with decreased food efficiency than wild type (WT) mice, with more pronounced effects in females. RNA sequencing performed on intestinal mucosa of Slfn3KO and WT mice showed gene ontology decreases in cell adhesion molecule signaling, tumor necrosis factor receptor binding, and adaptive immune cell proliferation/functioning genes in Slfn3KO mice, with greater effects in females. qPCR analysis of fatty acid metabolism genes, Pla2g4c, Pla2g2f, and Cyp3c55 revealed an increase in Pla2g4c, and a decrease in Pla2g2f in Slfn3KO females. Additionally, adipogenesis genes, Fabp4 and Lpl were decreased and ketogenesis gene Hmgcs2 was increased in female Slfn3KO mice. Sequencing did not reveal significant changes in differentiation markers, so qPCR was utilized. Slfn3KO tended to have decreased expression of intestinal differentiation markers sucrase isomaltase, dipeptidyl peptidase 4, villin 1, and glucose transporter 1 (Glut1) vs. WT males, although these trends did not achieve statistical significance unless data from several markers was pooled. Differentiation markers, Glut2 and sodium-glucose transporter 1 (SGLT1), did show statistically significant sex-dependent differences. Glut2 mRNA was reduced in Slfn3KO females, while SGLT1 increased in Slfn3KO males. Notch2 and Cdx2 were only increased in female Slfn3KO mice. Although Slfn3KO mice gain less weight and decreased food efficiency, their biochemical phenotype is more subtle and suggests a complex interplay between gender effects, Slfn3, and another regulatory pathway yet to be identified that compensates for the chronic loss of Slfn3.

SUBMITTER: Vomhof-DeKrey EE

PROVIDER: S-EPMC6602453 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Schlafen 3 knockout mice display gender-specific differences in weight gain, food efficiency, and expression of markers of intestinal epithelial differentiation, metabolism, and immune cell function.

Vomhof-DeKrey Emilie E EE Lee Jun J Lansing Jack J Brown Chris C Darland Diane D Basson Marc D MD

PloS one 20190701 7

Self-renewal and differentiation are essential for intestinal epithelium absorptive functioning and adaptation to pathological states such as short gut syndrome, ulcers, and inflammatory bowel disease. The rodent Slfn3 and its human analog Slfn12 are critical in regulating intestinal epithelial differentiation. We sought to characterize intestinal function in Slfn3 knockout (KO) mice. Male and female pair-fed Slfn3KO mice gained less weight with decreased food efficiency than wild type (WT) mice ...[more]

PMID: 31260507

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Project description:Studies have found that antipsychotics and antidepressants are associated with weight gain and obesity, particularly among women and some minority groups. Incarcerated populations (also referred to as offenders, prisoners or inmates) have a high prevalence of mental health problems and 15 % of offenders have been prescribed medications. Despite rates of antidepressant and antipsychotic use, investigations of weight gain and obesity in regard to these agents seldom have included offenders.This retrospective descriptive study (2005-2011) was conducted with a Department of Corrections in the east south central United States to investigate the relationship between antidepressant and antipsychotic agents, weight gain, obesity and race or gender differences. We sampled adult offenders who had an active record, at least two weight observations and height data. Offenders were classified into one of four mutually exclusive groups depending upon the type of medication they were prescribed: antidepressants, antipsychotics, other medications or no pharmacotherapy.The sample population for this study was 2728, which was 25.2 % of the total population. The population not on pharmacotherapy had the lowest baseline obesity rate (31.7 %) compared to offenders prescribed antipsychotics (43.6 %), antidepressants (43.6 %) or other medications (45.1 %). Offenders who were prescribed antidepressants or antipsychotics gained weight that was significantly different from zero, p?<?.001 and p?=?.019, respectively. Women in the antidepressant group gained 6.4 kg compared to 2.0 kg for men, which was significant (p?=?.007). Although women in the antipsychotic group gained 8.8 kg compared to 1.6 kg for men, the finding was not significant (p?=?.122). Surprisingly, there were no significant differences in weight gain between African Americans and Whites in regard to antidepressants (p?=?.336) or antipsychotic agents (p?=?.335).This study found that women and men offenders prescribed antidepressant or antipsychotic agents gained weight during their incarceration. Women prescribed antidepressants gained significantly more weight than men. However, there was no significant difference in weight gain between African Americans and Whites. Results suggest further investigation is needed to understand the effect of medication history, metabolic syndrome and to explain gender disparities.

Project description:ImportanceThe normal absorptive function and structural maintenance of the intestinal mucosa depend on a constant process of proliferation of enterocytic stem cells followed by progressive differentiation toward a mature phenotype. The mechanisms that govern enterocytic differentiation in the mucosa of the small intestine are poorly understood.ObjectiveTo determine whether schlafen 3 (but not other schlafen proteins) act in vivo and whether its effects are limited to the small intestine. We have previously demonstrated in nonmalignant rat intestinal IEC-6 cells that schlafen 3 levels correlate with the expression of various differentiation markers in vitro in response to differentiation stimuli.DesignRandomized controlled experiment.SettingAnimal science laboratory.ParticipantsMale Sprague-Dawley rats 8 to 13 weeks old.Main outcomes and measuresMessenger RNA (mRNA) from jejunal and colonic mucosa was isolated, and transcript levels of schlafen proteins 1, 2, 3, 4, 5, 13, and 14; sucrase isomaltase (SI); dipeptidyl peptidase 4 (Dpp4); glucose transporter type 2 (Glut2); and villin were measured by quantitative reverse transcriptase-polymerase chain reaction. We tested parallel variations in protein levels by Western blotting and Dpp4 enzyme activity.ResultsThe transcript level of schlafen 3 (Slfn3) correlated with the levels of the differentiation markers SI, Dpp4, Glut2, and villin. However, the expression of schlafen proteins 1, 2, 4, 5, 13, and 14 did not correlate with the expression of the differentiation markers. The mucosal mRNA levels of Slfn3, SI, Glut2, and Dpp4 were all substantially higher in the rat jejunum than in colonic mucosa by a mean (SE) factor of 51.0 (13.2) for 6 rats (P < .05), 599 (99) for 8 rats (P < .01), 12.5 (5.5) for 8 rats (P < .01), and 14.0 (3.9) for 8 rats (P < .01), respectively. In IEC-6 cells, infection with adenovirus-expressing GFP-tagged Slfn3 significantly increased Slfn3 expression and Dpp4-specific activity compared with GFP-expressing virus (in 6 rats; P < .05).Conclusions and relevanceTaken together with our previous in vitro observations, the results suggest that small intestinal enterocytic epithelial differentiation in rats may be regulated by Slfn3 in vivo, as in vitro, and that these effects may be specific to the small intestinal enterocytic phenotype as opposed to that of the mature colonocyte. Slfn3 human orthologs may be targeted to stimulate intestinal differentiation in patients with short bowel syndrome.

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Schlafen 3 knockout mice display gender-specific differences in weight gain, food efficiency, and expression of markers of intestinal epithelial differentiation, metabolism, and immune cell function.

Publications

Schlafen 3 knockout mice display gender-specific differences in weight gain, food efficiency, and expression of markers of intestinal epithelial differentiation, metabolism, and immune cell function.

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