Diabetes prevention is a large topic of research that is focused on nutritional and exercise‐based interventions with some genetic predisposition based interventions. FAT10 is a ubiquitin‐like protein and Type 1 Diabetes (T1D) susceptibility gene that may play a role in age‐related inflammation, adiposity, cancer, and kidney disease. The young T1D susceptible, LEW.1WR1 rat overexpresses FAT10 and has higher fasting concentrations of blood insulin. It is unclear how the overexpression of FAT10 effects directly affects insulin sensitivity, secretion, or production. It is also unclear if the initial insulin sensitivity of this animal model plays a role in disease susceptibility. Therefore we hypothesized that older LEW.1WR1 rats will have markers of increased insulin resistance like increased insulin and beta cell mass due to the poor regulation of FAT10 expression in this model. The objective of this study was to characterize insulin sensitivity, insulin levels, and characterize the relative beta cell size of adult LEW.1WR1 rats with or without dietary stress to understand if FAT10 expression plays a role in the regulation of inflammation and aging‐induced insulin resistance. To test this hypothesis we used LEW.1WR1 and LEW.SsNHsd rat and monitored weight gain and glucose tolerance over the course of 12 weeks on a high fat or control diet; we also isolated pancreata and used immunohistochemistry staining for insulin to analyze islet size and insulin staining. The LEW.ssNHsd rat served as a control rat because it does not have the alteration in the FAT10 promoter region. Glucose tolerance tests were performed prior to starting the diet as a baseline, and after 10 weeks on the diet to determine the effects of diet and aging on the rat groups in regards to Insulin Sensitivity. We observed that in the course of 10 weeks the control LEW.1WR1 rats became significantly more glucose intolerant and had increased insulin levels. The control LEW.1WR1 rats also gained weight at a rate similar to the high‐fat diet, a diet that is traditionally used to induce insulin resistance and glucose intolerance. This data suggests that FAT10 may be playing a role in age‐related adiposity, glucose intolerance, insulin sensitivity, and beta‐cell changes in the LEW.1WR1 rat. This study begins to lay the groundwork for understanding how alterations in FAT10 and metabolism increase T1D susceptibility.Support or Funding InformationThe University of Alabama in HuntsvilleLouis Stokes Alliance for Minority Participation (NSF)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

FAT10 is an ubiquitin-like protein and Type 1 Diabetes (T1D) susceptibility gene that may play a role in age-related inflammation, adiposity, and cancer risk. The LEW.1WR1(1WR1) rat overexpresses FAT10 and has higher fasting concentrations of blood insulin and triglyceride during the induction of T1D. FAT10 is hypothesized to play a role in the expression of adipogenic genes; however, it is unclear if overexpression of FAT10 directly affects insulin sensitivity and glucose metabolism. We hypothesize that young adult 1WR1 rats will have increased glucose intolerance due to the poor regulation of insulin secretion which over time leads to reduced insulin sensitivity and increased adiposity. To test this hypothesis, we monitored glucose and insulin tolerance by glucose (GTT) or insulin tolerance (ITT) test and weight gain throughout 12 weeks on high fat and high sucrose (HFD) or moderate sucrose (MS) diet. The LEW/ssNHsd (SsNHsd) rat serves as a control rat. All experiments contain seven rats per group. We observed that at four weeks, the HFD diet rat groups had increased but non-significant fasting blood glucose levels during an ITT (109 +/- 4 mg/dL 1WR1-MS; 113 +/- 5 mg/dL SsNHsd-MS; 132 +/- 6 mg/dL 1WR1 HFD; or 131 +/- 13 mg/dL SsNHsd-HFD.) At ten weeks, the 1WR1-MS rats were more glucose intolerant than the control SsNHsd-MS rat (311.7 +/- 64 mg/dL vs. 194 +/- 53 mg/dL; p=0.09.) We compared the eight week GTT of the 1WR1-MS rats to a GTT before starting the diets (zero weeks) and the thirty minute time points are significantly different for the 1WR1-MS after 8 weeks on the MS diet compared to both the 1WR1-MS and SsNHsd-MS prior to the MS diet ( 164 +/- 27 mg/dL zero weeks 1WR1; 167 +/- 26 mg/dL zero weeks SsNHsd; 311 +/-64 mg/dL eight weeks 1WR1-MS p< 0.0001). 1WR1 rats on both diets also gained weight at similar rates, yet the total abdominal fat mass of the 1WR1-MS rats was not increased compared to the SsNHsd-MS (17.43 +/- 3.48 g 1WR1-MS vs. 16.42 +/- 2.73 g SsNHsd-MS p=0.94 and 24.64 +/- 4.27 g 1WR1-HFD p=0.004) and 1WR1 rat epididymal fat was not significantly different between the two diets compared to the significant difference in SsNHsd rats groups (5.85+/-1.01 1WR1-MS vs. 7.27+/- 1.42 1WR1-HFD p=0.07; 4.63 +/- 0.81 vs. 6.77 +/- 0.65 p=0.0052.) This data suggests that metabolic shifts are occurring in the 1WR1 rat, due to either increased sucrose intake or aging. These shifts reflected the increased glucose intolerance after eight weeks and the changes in abdominal fat pads relative to body mass. This study lays the groundwork for characterizing how alterations in FAT10 increase metabolic dysfunction through aging, glucose metabolism, insulin secretion/signaling, and lipid metabolism/catabolism. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news confere...

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Post-traumatic stress disorder (PTSD) is a psychiatric disorder characterized by severe behavioral alterations, but also demonstrates elevated levels of systemic inflammation, sympathoexcitation, and a potentiated risk for autoimmune and cardiovascular diseases. These physiological changes suggest perturbations to the immune system, however, the signaling mechanisms linking psychological trauma to the immune system are not well understood. Utilizing a pre-clinical mouse model of PTSD known as repeated social defeat stress (RSDS), we previously demonstrated that psychological trauma causes robust T-lymphocyte-driven inflammation in the spleen as evidenced by increased pro-inflammatory cytokine production (primarily interleukin 17A, IL-17A), inflammatory polarization, and enhanced mitochondrial reactive oxygen species. Moreover, targeted denervation of the spleen was able to completely ablate this T-lymphocyte inflammatory response after psychological trauma, suggesting the signal was autonomic and neural in nature. Given that the splenic nerve possesses only sympathetic neurons (no direct parasympathetic innervation), we hypothesized that psychological trauma mediates splenic T-lymphocyte inflammation via enhanced release of sympathetic neurotransmitters. To test this, we first exposed naïve primary T-lymphocytes to various sympathetic catecholamines, including dopamine, norepinephrine, and epinephrine. Contrary to our original hypothesis, we observed no significant changes in IL-17A expression or mitochondria reactive oxygen species. Next, we assessed the physiological response of naïve T-lymphocytes exposed to neuropeptide Y (NPY) given its role in both sympathoexcitation as well as in PTSD. Interestingly, naïve T-lymphocytes treated with NPY also demonstrated no effect, but when NPY was given in combination of norepinephrine, we observed both an increase in IL-17A gene expression (~2 fold) and intracellular redox (~2 fold). To further investigate this effect, we examined NPY levels in our RSDS mouse model over-time. Circulating NPY levels spiked immediately after only one day of RSDS (~4.5 fold, p=0.0317) but steadily declined over the remaining 10 day psychological trauma induction. Intriguingly, NPY levels were strongly correlated with both circulating IL-17A and T-lymphocyte mitochondrial reactive oxygen species levels after RSDS, supporting our in vitro observations. Overall, these data suggest NPY may be playing a critical role in shaping the inflammatory milieu after psychological trauma, which may enhance the likelihood of inflammatory comorbidities. NIH R01HL158521 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.