The western diet (WD), which is rich in fat, carbohydrates, and refined sugars, is a major contributor to the global epidemic of metabolic syndrome in our modern society. Despite the well‐documented cardioprotection exhibited by the pre‐menopausal female population, studies have indicated that certain stressors may abolish this cardiovascular protection. Studies on the impact of the WD on the cardiometabolic profile of female cohorts remains limited. Lysine acetylation, a reversible posttranslational modification of histone and non‐histone proteins, has been closely associated with metabolic disorders. Based on these factors, we hypothesized that short‐term exposure to the WD alters cardiometabolic parameters in premenopausal rats and alters levels of lysine acetylation in the cardiovascular tissues. Adult female Wistar rats were randomized in two groups: Control Group (n=8) was assigned a regular chow diet and WD Group (n=12) received WD (40% fat, 43% carbohydrates, and 17% protein) for 17 weeks. Results showed that WD group exhibited increased body weight (376 ± 49 vs 305 ± 41g, p<0.05), periabdominal fat content (30 ±11 vs 11 ±2g, p<0.01), % body fat (8.1 ±1.0 vs 3.6 ±0.4%, p<0.01), and serum triglyceride levels (56 ± 13 vs 25 ± 4 mg/dl, p<0.01) compared to controls. Although the WD group exhibited significant increases in glucose intolerance (AUC: 17068.5 ± 730 vs. 13787.67± 814 a.u, p<0.01) and insulin resistance (HOMA‐IR: 5.75 ± 0.9 vs. 3.25 ± 0.62 control, p<0.05), no differences in fasting blood glucose and hemoglobin A1C were found. Using direct arterial blood pressure measurements via carotid artery catheterization, we observed increased systolic blood pressure (146.19 ±9.4 vs 126.22 ± 9.8 mmHg controls, p<0.001), which is contradictory with previous studies. Our vascular reactivity studies revealed that short‐term WD markedly impaired endothelial‐dependent relaxation. Additionally, using DHE staining we found that aortas from the WD group exhibited augmented levels of oxidative stress (3.1‐fold increase vs. control, p<0.001). Strikingly, levels of global lysine acetylation were markedly elevated in the aortas (2.2‐fold increase vs. control, p<0.01) and heart (1.4‐fold increase vs. control, p<0.05) of WD group. Levels of acetyltransferase PCAF were significantly upregulated in the aortas (2.2‐fold increase vs. control, p<0.05). Interestingly, PCAF and deacetylase HDAC9 expression was diminished in hearts from WD group (30% reduction vs. control, p<0.05) and (85% reduction vs. control, p<0.05), respectively. Besides these cardiovascular alterations, the WD also led to the development of non‐alcoholic fatty liver disease (NAFLD) and robust increases in hepatic global lysine acetylation (3.0‐fold increase vs. control, p<0.001). Taken together, our results demonstrated that, even under short‐term exposure, the WD negatively affects the metabolic and cardiovascular parameters of female rats and it is associated with elevated levels of global lysine acetylation in cardiometabolic tissues. This study will be further conducted to identify the specific proteins acetylated in blood vessels and heart from female population under WD regimes.Support or Funding InformationIn‐house Grant NYIT to MACSThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Background Obesity has become a prevalent public health issue, increasing the risk of cardiovascular diseases which are the leading cause of death in the US. A major contributor to the obesity epidemic is the chronic consumption of diets rich in saturated fat and sugar, known as western diet (WD). During obesity, PVAT loses its vasculo‐protective properties and becomes inflamed negatively impacting vascular function. Cx3cr1GFP/WT transgenic fluorescent mice that express a GFP reporter in microglia/macrophages, were utilized in this study to visualize macrophage infiltration in the PVAT from mice chronically exposed to a WD. Methods Adult homozygous male Cx3cr1GFP/WT mice were randomized to the control group (n=4) fed a regular chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose], and 24.1% protein) and the WD group (n=9) fed a WD (40% fat, 43% carbohydrates [34% sucrose], and 17% protein) for 52 weeks. Metabolic cage studies were performed to determine food and water intake, along with feces and urine output. Glucose metabolism was assessed by intraperitoneal glucose tolerance test (IPGTT). At the terminal experiments, direct measurements of arterial blood pressure were obtained by carotid catheterization, and aortas containing PVAT were collected for further histological analysis. Macrophage labeled by GFP in PVAT was visible by fluorescence microscopy and scored in a blind fashion. Results As expected, after over one year under WD conditions, Cx3cr1GFP/WT mice exhibited increased body weight (40.82 ± 2.09 vs. 33.83 ± 1.77g controls, p<0.05) and intolerance to glucose as demonstrated by increased blood glucose area under the curve during IPGTT (51828 ± 4562 vs. 28333 ± 3182 a.u, p<0.05). While the WD group showed decreased daily food consumption (1.36 ± 0.24 vs. 2.17 ± 0.10g controls, p<0.05), no differences in caloric consumption was observed between the groups (5.56 ± 2.78 vs 5.36 ± 1.37 kcals controls). Interestingly, the WD group exhibited decreased water intake (2.90 ± 0.92 vs. 5.13 ± 1.96 mL, p<0.05), urine output (0.56 ± 0.32 vs.1.69 ± 0.63 ml, p<0.01), and feces output (0.34 ± 0.10 vs.1.66 ± 0.30g, p<0.0001) compared to controls. Chronic exposure to WD also resulted in increased systolic blood pressure (119.1 ± 5 vs. 102.9 ± 4 mmHg, p<0.05) along with increased heart rate (481.2 ± 11.7 vs. 429.1 ± 24.6 bpm, p<0.05). Interestingly, PVAT from the WD group exhibited a white‐like adipose tissue feature comprising enlarged adipocytes, in contrast to their native brown‐like adipose tissue, characterizing a phenotypic modulation. Strikingly, GFP signal in the PVAT from the WD group was significantly augmented by 70% compared to controls (Figure 1), showing a robust infiltration of macrophages in the PVAT. Conclusion Our results suggest that increased infiltration of macrophages in PVAT after chronic consumption of a WD promotes inflamed PVAT which in turn may contribute to dysregulation of blood pressure. Further studies will be needed to fully characterize the negative impact of a WD in the PVAT and its cons...
Metabolic memory is a phenomenon by which the body remembers previous exposure to metabolic stressors, such as hyperglycemia. Consumption of a western diet (WD) is a major part of modern life contributing to the epidemic of Metabolic Syndrome (MS), a significant risk factor for cardiovascular disease. Recent studies from our laboratory have characterized a model of WD induced MS in female rats. If not treated early, MS often progresses to Type II Diabetes Mellitus (T2DM). Adopting a healthier diet prior to onset of T2DM may be sufficient to reverse the constellation of metabolic symptoms associated with MS including hyperglycemia, hypertriglyceridemia, and increased body fat around the waist. However, it remains unclear if this diet reversal overcomes metabolic memory and cardiovascular dysfunction associated with MS. We hypothesize that cardiovascular dysfunction will persist despite diet reversal due to the development of metabolic memory. Eight‐week old female Wistar rats were fed a WD (21% fat, 50% carbohydrate (34% sucrose), 20% protein) for 17 weeks (WD group) to induce MS. Then, the rats were subjected to diet reversal for 8 weeks (rWD group). The control group received a regular chow diet (5% fat, 48.7% carbohydrate (3.2% sucrose), 24.1% protein). Metabolic (body weight, triglycerides, free fatty acids, glucose tolerance) and cardiovascular (blood pressure and vascular reactivity) parameters were assessed. WD group showed increased body weight, triglyceride levels, and systolic blood pressure characterizing MS. Moreover, fatty liver was observed in the WD group. As expected, rWD group exhibited improvement of all metabolic parameters and reversal of fatty liver (Figure 1). WD group showed marked increases in systolic blood pressure, measured via right carotid catheterization. Using wire myography, cumulative concentration curves were performed for acetylcholine and sodium nitroprusside. We found a significant impairment of endothelium dependent and independent vasorelaxation, respectively. Surprisingly, the rWD group did not decrease blood pressure (Figure 2) or improve impaired vasorelaxation. These results indicate that WD causes long‐lasting cardiovascular complications that are not alleviated by diet reversal. Our findings show for the first time that exposure to a WD can lead to metabolic memory in the cardiovascular system. We will extend our studies to examine potential mechanisms of metabolic memory leading to persistent cardiovascular dysfunction.Support or Funding InformationIn‐house Grant NYITThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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