Abstract
Background: Diet-induced obesity (DIO) increases risk for cardiovascular disease largely due to compromised gut barrier integrity and systemic inflammation. Animal models for understanding the pathophysiology of complications associated with DIO do not take address the genetic factors, which determine the individual variation in the susceptibility to develop complications. Hypothesis: DO mice recapitulate the heterogeneity of western diet-induced metabolic syndrome, gut barrier disruption and systemic inflammation. Methods: DO mice were fed with either control (CD) or western diet (WD) (Teklad) (n = 10) for 16 weeks. Blood glucose levels, glucose tolerance and the intestinal permeability were determined. Inflammatory cells in the bone marrow or blood were characterized in basal conditions or in response to hindlimb ischemia (HLI). Blood flow recovery following HLI was measured by using Laser Doppler Imaging system and the intestinal-stem-cells (ISCs) were characterized by using markers, Lgr5, Olfm4 and Wnt3. Results: Wide variation in the weight gain, hyperglycemia and glucose tolerance in DO mice was observed following WD (n = 10). Similarly, wide variation was observed in Wnt3 expression and in the density of ISCs in colon of DO mice on WD. Heterogeneity in the ISC layer correlated with the variation in the intestinal permeability induced by WD compared to the CD ( p < 0.05, n = 10). The number of inflammatory cells (monocytes – CD45+Ly6G−Ly6C+CD115+, neutrophils - CD45+Ly6G+Ly6C+CD115−, pro-inflammatory macrophages - CD45+CD11b+Ly6G−Ly6C+F4/80+CCR2+CD80+ and anti-inflammatory macrophages - CD45+CD11b+Ly6G−Ly6C+F4/80+CX3CR1+CD206+) in the BM or blood showed heterogeneity in WD-DO mice in accordance with variability in the glucose tolerance. Accordingly, blood flow recovery following HLI showed wide variation with three mice on WD showing full recovery, which correlated with variability in the mobilization of inflammatory cells (n = 9). Conclusion: DO mouse model depicts human diversity in response to WD-induced changes in gut barrier integrity, inflammation and ischemic vascular repair therefore serves as a suitable model for evaluating pharmacological agents that would be effective in a diverse population. Jackson Laboratory Diversity Outbred Pilot Award National Institute of Aging (AG056881). This is the full abstract presented at the American Physiology Summit 2024 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.
Published Version
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