Browsing by Author "Casasnovas, Jose"

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    High Glucose Alters Fetal Rat Islet Transcriptome and Induces Progeny Islet Dysfunction
    (BioScientifica, 2019-02) Casasnovas, Jose; Jo, Yunhee; Rao, Xi; Xuei, Xiaoling; Brown, Mary E.; Kua, Kok Lim; Pediatrics, School of Medicine
    Offspring of diabetic mothers are susceptible to developing type 2 diabetes due to pancreatic islet dysfunction. However, the initiating molecular pathways leading to offspring pancreatic islet dysfunction are unknown. We hypothesized that maternal hyperglycemia alters offspring pancreatic islet transcriptome and negatively impacts offspring islet function. We employed an infusion model capable of inducing localized hyperglycemia in fetal rats residing in the left uterine horn, thus avoiding other factors involved in programming offspring pancreatic islet health. While maintaining euglycemia in maternal dams and right uterine horn control fetuses, hyperglycemic fetuses in the left uterine horn had higher serum insulin and pancreatic beta cell area. Upon completing infusion from GD20 to 22, RNA sequencing was performed on GD22 islets to identify the hyperglycemia-induced altered gene expression. Ingenuity pathway analysis of the altered transcriptome found that diabetes mellitus and inflammation/cell death pathways were enriched. Interestingly, the downregulated genes modulate more diverse biological processes, which includes responses to stimuli and developmental processes. Next, we performed ex and in vivo studies to evaluate islet cell viability and insulin secretory function in weanling and adult offspring. Pancreatic islets of weanlings exposed to late gestation hyperglycemia had decreased cell viability in basal state and glucose-induced insulin secretion. Lastly, adult offspring exposed to in utero hyperglycemia also exhibited glucose intolerance and insulin secretory dysfunction. Together, our results demonstrate that late gestational hyperglycemia alters the fetal pancreatic islet transcriptome and increases offspring susceptibility to developing pancreatic islet dysfunction.
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    Offspring of Obese Dams Exhibit Sex-Differences in Pancreatic Heparan Sulfate Glycosaminoglycans and Islet Insulin Secretion
    (Frontiers Media, 2021-05-24) Casasnovas, Jose; Damron, Christopher Luke; Jarrell, James; Orr, Kara S.; Bone, Robert N.; Archer-Hartmann, Stephanie; Azadi, Parastoo; Kua, Kok Lim; Pediatrics, School of Medicine
    Offspring of obese mothers suffer higher risks of type 2 diabetes due to increased adiposity and decreased β cell function. To date, the sex-differences in offspring islet insulin secretion during early life has not been evaluated extensively, particularly prior to weaning at postnatal day 21 (P21). To determine the role of maternal obesity on offspring islet insulin secretion, C57BL/6J female dams were fed chow or western diet from 4 weeks prior to mating to induce maternal obesity. First, offspring of chow-fed and obese dams were evaluated on postnatal day 21 (P21) prior to weaning for body composition, glucose and insulin tolerance, and islet phasic insulin-secretion. Compared to same-sex controls, both male and female P21 offspring born to obese dams (MatOb) had higher body adiposity and exhibited sex-specific differences in glucose tolerance and insulin secretion. The male MatOb offspring developed the highest extent of glucose intolerance and lowest glucose-induced insulin secretion. In contrast, P21 female offspring of obese dams had unimpaired insulin secretion. Using SAX-HPLC, we found that male MatOb had a decrease in pancreatic heparan sulfate glycosaminoglycan, which is a macromolecule critical for islet health. Notably, 8-weeks-old offspring of obese dams continued to exhibit a similar pattern of sex-differences in glucose intolerance and decreased islet insulin secretion. Overall, our study suggests that maternal obesity induces sex-specific changes to pancreatic HSG in offspring and a lasting effect on offspring insulin secretion, leading to the sex-differences in glucose intolerance.
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    SAT-158 Offspring Exposed to Maternal High Fat Diet Exhibits Systemic Inflammation and Pancreatic Islet Dysfunction
    (Oxford University Press, 2019-04-15) Casasnovas, Jose; Pineros, Annie; Jarrell, James; Kua, Kok Lim; Pediatrics, School of Medicine
    Offspring born to overweight mothers are more likely to develop dysregulated immune response1, obesity1 and pancreatic islet dysfunction2. These offspring have increased inflammation at birth3 and at least until childhood4. We hypothesize that heightened inflammation in offspring of overweight mothers increases offspring risks of pancreatic islet dysfunction. We induced maternal overweight by providing 45% high fat diet (HFD) to female mice 2 - 4 weeks before pregnancy until weaning. When compared to controls, P21 weanlings of HFD mothers had impaired glucose tolerance in dose and gender dependent manner [GTT AUC: male 2-week HFD* 30 ± 6% higher; male 4-week HFD* 37± 3% higher: 9-11/group; female 2-week HFD 13 ± 5% higher; female 4-week HFD* 22 ± 3% higher: 3-9/group, *p<0.05 compared to controls]. Glucose intolerance persisted in 8-week-old male from 2-week HFD mothers (p<0.05, n=6-9/group), with decreased pancreatic islets glucose induced calcium response measured using Fura-2AM calcium imaging (F1/F0 Con:2.00 ± 0.06, HFD2W: 1.69±0.12*, HFD4w: 0.71±0.09*, n =3/group). Cytokines production in the serum, macrophage response and metabolic phenotypes of offspring were assessed on postnatal day 21 (P21) and at 8 weeks old. Compared to control pups, weanling of HFD mothers had elevated serum/plasma IL-1b level along with increased polarization of M1 macrophages and decreased M2 macrophages, as well as an increase of IL-1b secretion in LPS-stimulated macrophages. At 8 weeks of age, HFD male offspring had increased activation markers of splenic dendritic cells indicating a development of systemic inflammatory response early in life. Taken together, our findings suggest that mice offspring from HFD mothers have pancreatic dysfunction, and an inflammatory response. This work is funded by the Riley Children’s Foundation. 1. Kelishadi, R., Roufarshbaf, M., Soheili, S., Payghambarzadeh, F. & Masjedi, M. Association of Childhood Obesity and the Immune System: A Systematic Review of Reviews. Child. Obes. Print 13, 332-346 (2017). 2. Graus-Nunes, F. et al. Pregestational maternal obesity impairs endocrine pancreas in male F1 and F2 progeny. Nutrition 31, 380-387 (2015). 3. Dosch, N. C. et al. Maternal Obesity Affects Inflammatory and Iron Indices in Umbilical Cord Blood. J. Pediatr. 172, 20-28 (2016). 4. Leibowitz, K. L. et al. Maternal obesity associated with inflammation in their children. World J. Pediatr. WJP 8, 76-79 (2012).
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    Sex discrepancy in the reduction of mucosal‐associated invariant T cells caused by obesity
    (Wiley, 2021-03-09) Liu, Jianyun; Nan, Hongmei; Brutkiewicz, Randy R.; Casasnovas, Jose; Kua, Kok Lim; Microbiology and Immunology, School of Medicine
    Introduction: Gut microbiota has been reported to contribute to obesity and the pathology of obesity-related diseases but the underlying mechanisms are largely unknown. Mucosal-associated invariant T (MAIT) cells are a unique subpopulation of T cells characterized by the expression of a semi-invariant T cell receptor (TCR) α chain (Vα19 in mice; Vα7.2 in humans). The expansion and maturation of MAIT cells require the gut microbiota and antigen-presenting molecule MR1, suggesting that MAIT cells may play a unique role in bridging gut microbiota, obesity, and obesity-associated inflammation. Methods: The levels of human MAIT cells from obese patients, as well as mouse MAIT cells from obese mouse models, were determined by flow cytometry. By comparing to controls, we analyzed the change of MAIT cells in obese subjects. Results: We found obese patients had fewer circulating MAIT cells than healthy-weight donors and the difference was more distinct in male patients. Consistently, male mice (but not female mice) have shown reduced MAIT cells in the liver and adipose tissue after a 10-week Western diet compared to mice on a control diet. We also explored the possibility of utilizing high-throughput technology (i.e., quantitative polymerase chain reaction [qPCR]), other than flow cytometry, to determine the expression levels of the invariant TCR of human MAIT cells. But a minimal correlation (R2 = 0.23, p = .11) was observed between qPCR and flow cytometry data. Conclusion: Our study suggests that there is a sex discrepancy in the impact of obesity on MAIT cells: MAIT cells in male (but not female) humans and male mice are reduced by obesity.