Standard Western Diet Research Articles

Pyridoxamine Alleviates Cardiac Fibrosis and Oxidative Stress in Western Diet-Induced Prediabetic Rats.

Individuals with type 2 diabetes mellitus (T2DM) are at an increased risk for heart failure, yet preventive cardiac care is suboptimal in this population. Pyridoxamine (PM), a vitamin B6 analog, has been shown to exert protective effects in metabolic and cardiovascular diseases. In this study, we aimed to investigate whether PM limits adverse cardiac remodeling and dysfunction in rats who develop T2DM. Male rats received a standard chow diet or Western diet (WD) for 18 weeks to induce prediabetes. One WD group received additional PM (1 g/L) via drinking water. Glucose tolerance was assessed with a 1 h oral glucose tolerance test. Cardiac function was evaluated using echocardiography and hemodynamic measurements. Histology on left ventricular (LV) tissue was performed. Treatment with PM prevented the increase in fasting plasma glucose levels compared to WD-fed rats (p < 0.05). LV cardiac dilation tended to be prevented using PM supplementation. In LV tissue, PM limited an increase in interstitial collagen deposition (p < 0.05) seen in WD-fed rats. PM tended to decrease 3-nitrotyrosine and significantly lowered 4-hydroxynonenal content compared to WD-fed rats. We conclude that PM alleviates interstitial fibrosis and oxidative stress in the hearts of WD-induced prediabetic rats.

Maternal macronutrient intake effects on offspring macronutrient targets and metabolism.

Exposure in utero to maternal diet can program offspring health and susceptibility to disease. Using C57BL6/JArc mice, we investigated how maternal dietary protein to carbohydrate balance influences male and female offspring appetite and metabolic health. Dams were placed on either a low-protein (LP) or high-protein (HP) diet. Male and female offspring were placed on a food choice experiment post weaning and were then constrained to either a standard diet or Western diet. Food intake, body weight, and composition were measured, and various metabolic tests were performed at different timepoints. Offspring from mothers fed HP diets selected a higher protein intake and had increased body weight in early life relative to offspring from LP diet-fed dams. As predicted by protein leverage theory, higher protein intake targets led to increased food intake when offspring were placed on no-choice diets, resulting in greater body weight and fat mass. The combination of an HP maternal diet and a Western diet further exacerbated this obesity phenotype and led to long-term consequences for body composition and metabolism. This work could help explain the association between elevated protein intake in humans during early life and increased risk of obesity in childhood and later life.

Walnut consumption and gut microbial metabolism: Results of an exploratory analysis from a randomized, crossover, controlled-feeding study

The effect of walnut-related modulation of gut microbiota composition on microbiota functionality is unknown. The aim was to characterize the effect of a walnut-enriched diet (WD), compared to a fatty acid-matched diet devoid of walnuts (WFMD) and a diet where oleic acid replaces alpha-linolenic acid (ORAD), on bacterial gene expression. A 3-period, randomized, crossover, controlled-feeding study was conducted. Participants were provided a 2-week run-in standard western diet (SWD; 50% kcal carbohydrate, 16% protein, 34% fat, 12% SFA). Following the SWD in random sequence order, participants were provided the WD, WFMD, and ORAD (48% carbohydrate; 17% protein; fat 35%; 7% SFA). The WD contained 18% of energy from walnuts (57g/d/2100kcal). The WFMD and ORAD were devoid of walnuts; liquid non-tropical plant oils were included in these diets. Metatranscriptomic analyses were performed as an exploratory outcome. The analytical sample included 35 participants (40% female) with a mean±SD age of 43±10y and BMI of 30.3±4.9kg/m2. The ⍺-diversity of taxa actively expressing genes, assessed by observed species (p=0.27) and Pielou's Evenness (p=0.09), did not differ among the diets. The ⍺-diversity of actively expressed genes was greater following the WD compared to the WFMD and ORAD as assessed by the observed genes and Pielou's Evenness metrics (p<0.05). β-Diversity of the actively expressed genes differed following the WD compared to the WFMD (p=0.001) and ORAD (p=0.001); β-diversity did not differ between the WFMD and ORAD. Active composition analyses showed increased Gordonibacter (p<0.001) activity following the WD vs. the ORAD. Greater expression of many genes was observed following the WD compared to the WFMD and ORAD. Following the WD, greater expression of metabolism-related genes encoding glycine amidinotransferase (GATM; K00613) and arginine deiminase (K01478) was observed compared to the WFMD. Greater expression of glycine amidinotransferase (GATM; K00613) by Gordonibacter was also observed following the WD vs. the WFMD and ORAD. Our results suggest walnut intake may increase endogenous production of homoarginine through gut microbiota-mediated upregulation of GATM, which is a novel mechanism by which walnuts may lower cardiovascular disease risk. However, given the exploratory nature replication is needed. Clinicaltrials.gov (NCT02210767).

Moderate- and High-Intensity Endurance Training Alleviate Diabetes-Induced Cardiac Dysfunction in Rats.

Exercise training is an encouraging approach to treat cardiac dysfunction in type 2 diabetes (T2DM), but the impact of its intensity is not understood. We aim to investigate whether and, if so, how moderate-intensity training (MIT) and high-intensity interval training (HIIT) alleviate adverse cardiac remodeling and dysfunction in rats with T2DM. Male rats received standard chow (n = 10) or Western diet (WD) to induce T2DM. Hereafter, WD rats were subjected to a 12-week sedentary lifestyle (n = 8), running MIT (n = 7) or HIIT (n = 7). Insulin resistance and glucose tolerance were assessed during the oral glucose tolerance test. Plasma advanced glycation end-products (AGEs) were evaluated. Echocardiography and hemodynamic measurements evaluated cardiac function. Underlying cardiac mechanisms were investigated by histology, western blot and colorimetry. We found that MIT and HIIT lowered insulin resistance and blood glucose levels compared to sedentary WD rats. MIT decreased harmful plasma AGE levels. In the heart, MIT and HIIT lowered end-diastolic pressure, left ventricular wall thickness and interstitial collagen deposition. Cardiac citrate synthase activity, mitochondrial oxidative capacity marker, raised after both exercise training modalities. We conclude that MIT and HIIT are effective in alleviating diastolic dysfunction and pathological cardiac remodeling in T2DM, by lowering fibrosis and optimizing mitochondrial capacity.

Insulin Resistance and Hypertension: Mechanisms Involved and Modifying Factors for Effective Glucose Control.

Factors such as aging, an unhealthy lifestyle with decreased physical activity, snacking, a standard Western diet, and smoking contribute to raising blood pressure to a dangerous level, increasing the risk of coronary artery disease and heart failure. Atherosclerosis, or aging of the blood vessels, is a physiological process that has accelerated in the last decades by the overconsumption of carbohydrates as the primary sources of caloric intake, resulting in increased triglycerides and VLDL-cholesterol and insulin spikes. Classically, medications ranging from beta blockers to angiotensin II blockers and even calcium channel blockers were used alone or in combination with lifestyle modifications as management tools in modern medicine to control arterial blood pressure. However, it is not easy to control blood pressure or the associated complications. A low-carbohydrate, high-fat (LCHF) diet can reduce glucose and insulin spikes, improve insulin sensitivity, and lessen atherosclerosis risk factors. We reviewed articles describing the etiology of insulin resistance (IR) and its impact on arterial blood pressure from databases including PubMed, PubMed Central, and Google Scholar. We discuss how the LCHF diet is beneficial to maintaining arterial blood pressure at normal levels, slowing down the progression of atherosclerosis, and reducing the use of antihypertensive medications. The mechanisms involved in IR associated with hypertension are also highlighted.

Selenium, Zinc, and Copper Status of Vegetarians and Vegans in Comparison to Omnivores in the Nutritional Evaluation (NuEva) Study.

Plant-based diets usually contain more nutrient-dense foods such as vegetables, legumes, whole grains, and fruits than a standard Western diet. Yet, the amount and especially the bioavailability of several nutrients, such as trace elements, is supposed to be lower in comparison to diets with consumption of animal-derived foods. Based on this, the Nutritional Evaluation (NuEva) study (172 participants) was initiated to compare the trace element status of omnivores, flexitarians, vegetarians, and vegans. Serum selenium, zinc, and copper concentrations and biomarkers were evaluated at baseline and during a 12-month intervention with energy- and nutrient-optimized menu plans. The implementation of optimized menu plans did not substantially influence the status of trace elements. At baseline, serum selenium biomarkers were lower in vegetarians and vegans compared to omnivores and flexitarians. The zinc intake of vegetarians and vegans was significantly lower compared to omnivores, whereas the Phytate Diet Score was increased. Accordingly, total serum zinc concentrations were reduced in vegans which was, however, only significant in women and was further supported by the analysis of free zinc. Regarding copper status, no differences were observed for total serum copper. Overall, we identified selenium and zinc as critical nutrients especially when maintaining a vegan diet.

Whole-food plant-based diet reduces daytime sleepiness in patients with OSA

Consumption of a diet high in saturated fat has been associated with daytime sleepiness. A whole-food plant-based (WFPB) dietary pattern, which is low in saturated fat, has been shown to be beneficial in a variety of health conditions. We assessed the effect of a short-term (21 days) WFPB diet intervention on daytime sleepiness in 14 patients with obstructive sleep apnea (OSA). We found a mean decrease of 3.8 points (SD = 3.3, p = 0.003) on the Epworth Sleepiness Scale (ESS) after switching from a standard Western diet to a WFPB diet. Our results suggest that a WFPB diet could be a viable dietary intervention to reduce symptom of daytime sleepiness.

Nutrient Intake and Dietary Acid Load of Special Diets in the NHANES: A Descriptive Analysis (2009-2018).

Western diets are characterized by a high dietary acid load (DAL), which has been associated with adverse clinical outcomes, including type-2-diabetes and metabolic syndrome. Effective dietary strategies to lower DAL are urgently warranted. Plant-based diets (PBD), including vegetarian and vegan diets, are an effective measure to reduce DAL. Notably, not every individual wishes to adopt a PBD. Instead, many people rely on special diets promising comparable health benefits. The effects of those diets on DAL have rarely been investigated. Using data from the National Health and Nutrition Examination Surveys, we aimed to quantify DAL and nutrient intake in the most popular special diets in the United States, including weight-loss, low fat, low salt, low sugar, and diabetic diets. Our analysis included 3552 individuals on a special diet. The most popular diets were the weight-loss diet (n = 1886 individuals) and the diabetic diet (n = 728). Energy intake was below 2000 kcal/d for all diets; however, there were no statistically significant intergroup differences. DAL scores were positive for all special diets (>9 mEq/d), suggesting acidifying properties. Acid load scores of special diets did not differ significantly and were comparable to a standard Western diet. None of the examined diets was associated with alkaline properties.

RETRACTED: Bacillus Subtilis DE111 Improves Endothelial Dependent Vascular Dilation in Mice Fed a Western Diet

Vascular dysfunction often precedes the development of cardiovascular disease in which data from our lab and others suggest a role of the gut microbiome in the development of this defect. In a pilot study of healthy humans, we observed that the spore‐based probiotic, Bacillus Subtilis DE111(DE111), improved reactive hyperemia index (RHI) scores, indicating improved vascular dilation. To further explore whether DE111 impacts cardiovascular function, the current study examined its efficacy in a diet‐induced obesity model in mice. Male C57/BJ mice were fed a standard diet (SD; n=24) or Western diet (WD; n=24) for 8 weeks to induce vascular dysfunction and were then further divided such that (n=12) half of the animals on each diet received 1billion colony forming units per day (CFU/d) of DE111. Weekly body weight was measured until termination at 6 months of age. WD and WD+DE111 mice exhibited similar increases in body weight (SD: 31.2±2.3 vs WD: 47.4±3.3 and WD+DE111: 45.7±4.0) and impairments in glucose tolerance compared to SD mice (SD: 237.1±68.0 vs WD: 410±26.9 and WD+DE111: 460±116.8, p&lt;0.05). A 28% decrease in vessel dilation was observed with mice on a WD as compared to mice on a SD after addition of the endothelial‐dependent dilator acetylcholine (AUC, 918.3±49.25, p&lt;0.05). However, the addition of DE111 improved endothelial mediated vessel dilation in mice fed a WD+DE111 (AUC, 991.7±47.9, p&lt;0.05). This increase was observed independent of body weight changes and improvement in glucose tolerance. In conclusion, the addition of DE111 increased endothelial‐dependent dilation in mice fed a WD. Further analyses are underway to establish the mechanisms of this gut‐vasculature crosstalk, but our animal and human studies both suggest that the novel probiotic, DE111 may support cardiovascular health.

RNA-sequencing revealed apple pomace ameliorates expression of genes in the hypothalamus associated with neurodegeneration in female rats fed a Western diet during adolescence to adulthood

ABSTRACT Objectives Apple pomace, a waste byproduct of apple processing, is rich in nutrients (e.g. polyphenols and soluble fiber) with the potential to be neuroprotective. The aim of this study was to employ RNA-sequencing (RNASeq) technology to investigate diet-gene interactions in the hypothalamus of rats after feeding a Western diet calorically substituted with apple pomace. Methods Adolescent (age 21–29 days) female Sprague–Dawley rats were randomly assigned (n = 8 rats/group) to consume either a purified standard diet, Western (WE) diet, or Western diet calorically substituted with 10% apple pomace (WE/AP) for 8 weeks. RNA-seq was performed (n = 5 rats/group) to determine global differentially expressed genes in the hypothalamus. Results RNA-seq results comparing rats fed WE to WE/AP revealed 15 differentially expressed genes in the hypothalamus. Caloric substitution of WE diet with 10% apple pomace downregulated (q < 0.06) five genes implicated in brain aging and neurodegenerative disorders: synuclein alpha, phospholipase D family member 5, NADH dehydrogenase Fe-S protein 6, choline O-acetyltransferase, and frizzled class receptor 6. Discussion Altered gene expression of these five genes suggests that apple pomace ameliorated synthesis of the neurotransmitter, acetylcholine, in rats fed a WE diet. Apple pomace, a rich source of antioxidant polyphenols and soluble fiber, has been shown to reverse nonalcoholic fatty liver disease (NAFLD). Diet-induced NAFLD decreases hepatic de novo synthesis of choline, a precursor to acetylcholine. Based on preclinical evidence, apple pomace has the potential to be a sustainable functional food for maintaining brain function and for reducing the risk of neurodegeneration.

Nox2 Deficiency Reduces Cartilage Damage and Ectopic Bone Formation in an Experimental Model for Osteoarthritis

Osteoarthritis (OA) is a destructive disease of the joint with age and obesity being its most important risk factors. Around 50% of OA patients suffer from inflammation of the synovial joint capsule, which is characterized by increased abundance and activation of synovial macrophages that produce reactive oxygen species (ROS) via NADPH-oxidase 2 (NOX2). Both ROS and high blood levels of low-density lipoprotein (LDL) are implicated in OA pathophysiology, which may interact to form oxidized LDL (oxLDL) and thereby promote disease. Therefore, targeting NOX2 could be a viable treatment strategy for OA. Collagenase-induced OA (CiOA) was used to compare pathology between wild-type (WT) and Nox2 knockout (Nox2−/−) C57Bl/6 mice. Mice were either fed a standard diet or Western diet (WD) to study a possible interaction between NOX2-derived ROS and LDL. Synovial inflammation, cartilage damage and ectopic bone size were assessed on histology. Extracellular ROS production by macrophages was measured in vitro using the Amplex Red assay. Nox2−/− macrophages produced basal levels of ROS but were unable to increase ROS production in response to the alarmin S100A8 or the phorbol ester PMA. Interestingly, Nox2 deficiency reduced cartilage damage, synovial lining thickness and ectopic bone size, whereas these disease parameters were not affected by WD-feeding. These results suggest that NOX2-derived ROS are involved in CiOA development.

Histological investigation of the effects of western diet on pressure wound healing period

Objective: The stages of skin wound healing are a dynamic process and it is thought to be related to nutrition. Carbohydrates, proteins and fats have particular importance in different periods of recovery process. Our study has aimed to examine the effects of a western diet with high protein, fat, and carbohydrate content on pressure ulcer healing.&#x0D; Material and Methods: In this study, we used 22 healthy male Sprague Dawley rats weighing 100-185 g. We randomly divided the rats into two groups. The rats were fed according to the indicated diets (standard diet and western diet). On the first day of the fourth week, ischemia skin by histopathological examinations of the wound tissue samples on the 7th and 14th days of the wound healing period.&#x0D; Results: Statistically significant differences were observed in histological and immunohistochemical parameters in the tissue samples on the 7th and 14th days. On the 7th day, there were re-epithelialization (P=0.003), granulation cell density (P=0.004), inflammation (P=0.004), and angiogenesis (P= 0.003). We found re-epithelialization (P=0.001), granulation cell density (P=0.002), inflammation (P=0.002), and angiogenesis (P=0.001) on the 14th day. On the 7th and 14th days, we found the p-value between Ki-67 immunohistochemical staining percentages as P= 0.003 and the p-value for VEGF as P=0.002.&#x0D; Conclusion: We determined that in short-term wound healing, the western type diet was more effective on pressure wound healing than the standard diet.

Abstract P147: Dietary Protein Elicits A Leucine-mediated Threshold Effect On Monocyte/macrophage Mtorc1-autophagy Signaling Resulting In Elevated Cardiovascular Risk

High-protein intake is common in Western societies and generally considered healthy. However, results from some epidemiological studies suggest elevated protein intake is associated with increased risk for ischemic cardiovascular diseases. In addition, results from studies conducted in mice show that a high protein, compared with a standard Western diet, increases atherosclerosis burden and lesion complexity. The adverse effect of protein ingestion on plaque biology in mice is mediated by amino acid-mammalian target of rapamycin (mTOR)-dependent inhibition of autophagy in macrophages. Here, we evaluate the effect of graded amounts of protein ingestion on this amino acid-mTORC1-autophagy mechanism in human monocytes/macrophages and identify leucine as the key amino acid responsible for activating mTORC1 in macrophages. We describe the presence of a threshold effect of high protein intake on this deleterious signaling pathway wherein protein content greater than about 22% of total energy, which is consumed by nearly 1/4 th of the population in Western societies, acutely activates mTORC1 signaling in monocytes/macrophages. Furthermore, we identify leucine as the critical amino acid modulator and threshold indicator, capable of the dose-dependent mTORC1 activation and downstream functional effects. Finally, by designing specific mouse diets with protein contents mimicking graded levels of protein ingestion in our study participants, we demonstrate the presence of a dietary protein threshold effect in driving atherosclerosis in mouse models. These data demonstrate the potential deleterious impact of excessive protein intake on macrophages and atherosclerotic plaque progression.

Effects of a low-carbohydrate ketogenic diet on reported pain, blood biomarkers and quality of life in patients with chronic pain: A pilot randomised clinical trial rationale, study design and protocol

IntroductionA ketogenic diet has been shown to influence the nervous system and can potentially improve maladaptive changes occurring with chronic pain, specifically neuroinflammation and nervous system sensitisation. However, there is limited research on whether altering a standard western diet high in ultra-processed foods to a well-formulated ketogenic diet (WFKD) may reduce chronic pain. The aim of this clinical trial is to evaluate the effects of a WFKD on patients with chronic pain. MethodsThis is a 12-week pilot randomised clinical trial of adults with chronic musculoskeletal pain. All participants will commence with a 3-week run in whole-foods diet removing ultra-processed foods. At week 4 they will be randomised to either continue the whole food diet or start a WFKD (carbohydrate intake <50g/day). Finger prick ketone testing will evaluate the level of nutritional ketosis, and carbohydrate levels adjusted accordingly to achieve the target ketone level 0.5–3.0 mmol/L. Reported chronic pain levels, blood ketone levels, metabolic markers, inflammation and quality of life will be measured at baseline, post-intervention, and 3- months follow-up. ConclusionThis trial will evaluate the effects of a whole-food well formulated ketogenic diet on chronic pain perception. It attempts to address the commonalties between reported dietary approaches (diet quality and nutrient density) by using a comparator of equal food quality to allow the clinical evaluation of the ketogenic diet specifically on pain mechanisms. It will further the research on how a ketogenic diet may modulate physiology linked to chronic pain mechanisms such as metabolic dysregulation and inflammation.

Timed restricted feeding in adult rats using standard chow or Western diet causes different response to food behavior

ABSTRACT The study performed the temporal restriction of the circadian cycle of food in rats using standard chow or Westernized diet to assess feeding behavior and physiological parameters. Forty weaned male Wistar rats were divided into two groups: standard chow diet (C, n = 20) or an experimental diet Westernized (W, n = 20). At 60 days rats were distributed into four groups: C- Control; RC- Restricted control; W- Westernized; RW- Restricted Westernized. Restricted animals had access to food for 4 hours in the dark phase. The pattern of food intake, behavioral sequence of satiety (BSS), acute test of food preference, weight and abdominal fat were analyzed. The use of Westernized diet ad libitum increased body weight and ectopic abdominal fat, and reduced food and energy intake. Both interventions, food restriction and Westernized diet, altered BSS (accelerated of the satiety, reduced the size of the meal and increased feed rate). The food restriction modified food preference. The results in the present study indicate that the alteration in feeding schedules and/or Westernized diet are factors that modify feeding behavior, macronutrient preference, body weight and abdominal fat storage. These findings may contribute to the control of the onset of obesity and metabolic disorders.

The Immunopathogenesis of Alzheimer's Disease Is Related to the Composition of Gut Microbiota.

The microbiota–gut–brain axis plays an important role in the development of neurodegenerative diseases. Commensal and pathogenic enteric bacteria can influence brain and immune system function by the production of lipopolysaccharides and amyloid. Dysbiosis of the intestinal microbiome induces local and consecutively systemic immune-mediated inflammation. Proinflammatory cytokines then trigger neuroinflammation and finally neurodegeneration. Immune-mediated oxidative stress can lead to a deficiency of vitamins and essential micronutrients. Furthermore, the wrong composition of gut microbiota might impair the intake and metabolization of nutrients. In patients with Alzheimer’s disease (AD) significant alterations of the gut microbiota have been demonstrated. Standard Western diet, infections, decreased physical activity and chronic stress impact the composition and diversity of gut microbiota. A higher abundancy of “pro-inflammatory” gut microbiota goes along with enhanced systemic inflammation and neuroinflammatory processes. Thus, AD beginning in the gut is closely related to the imbalance of gut microbiota. Modulation of gut microbiota by Mediterranean diet, probiotics and curcumin can slow down cognitive decline and alter the gut microbiome significantly. A multi-domain intervention approach addressing underlying causes of AD (inflammation, infections, metabolic alterations like insulin resistance and nutrient deficiency, stress) appears very promising to reduce or even reverse cognitive decline by exerting positive effects on the gut microbiota.

Dietary Interventions Are Beneficial for Patients with Chronic Pain: A Systematic Review with Meta-Analysis.

The standard Western diet is high in processed hyperpalatable foods that displace nutrient-dense whole foods, leading to inflammation and oxidative stress. There is limited research on how these adverse metabolic drivers may be associated with maladaptive neuroplasticity seen in chronic pain and whether this could be attenuated by a targeted nutritional approach. The aim of this study was to review the evidence for whole-food dietary interventions in chronic pain management. A structured search of eight databases was performed up to December 2019. Two independent reviewers screened studies and evaluated risk of bias by using the National Institutes of Health assessment tool for controlled or pre-post studies and the Joanna Briggs checklist for case reports. A meta-analysis was performed in Review Manager. Forty-three studies reporting on 48 chronic pain groups receiving a whole-food dietary intervention were identified. These included elimination protocols (n = 11), vegetarian/vegan diets (n = 11), single-food changes (n = 11), calorie/macronutrient restriction (n = 8), an omega-3 focus (n = 5), and Mediterranean diets (n = 2). A visual analog scale was the most commonly reported pain outcome measure, with 17 groups reporting a clinically objective improvement (a two-point or 33% reduction on the visual analog scale). Twenty-seven studies reported significant improvement on secondary metabolic measures. Twenty-five groups were included in a meta-analysis that showed a significant finding for the effect of diet on pain reduction when grouped by diet type or chronic pain type. There is an overall positive effect of whole-food diets on pain, with no single diet standing out in effectiveness. This suggests that commonalities among approaches (e.g., diet quality, nutrient density, weight loss) may all be involved in modulating pain physiology. Further research linking how diet can modulate physiology related to pain (such as inflammation, oxidative stress, and nervous system excitability) is required.

The marine compound and elongation factor 1A1 inhibitor, didemnin B, provides benefit in western diet-induced non-alcoholic fatty liver disease

Inhibition of eukaryotic elongation factor 1A1 (EEF1A1) with the marine compound didemnin B decreases lipotoxic HepG2 cell death in vitro and improves early stage non-alcoholic fatty liver disease (NAFLD) in young genetically obese mice. However, the effects of didemnin B on NAFLD in a model of long-term diet-induced obesity are not known. We investigated the effects of didemnin B on NAFLD severity and metabolic parameters in western diet-induced obese mice, and on the cell types that contribute to liver inflammation and fibrosis in vitro. Male 129S6 mice were fed either standard chow or western diet for 26 weeks, followed by intervention with didemnin B (50 μg/kg) or vehicle by intraperitoneal (i.p.) injection once every 3 days for 14 days. Didemnin B decreased liver and plasma triglycerides, improved oral glucose tolerance, and decreased NAFLD severity. Moreover, didemnin B moderately increased hepatic expression of genes involved in ER stress response (Perk, Chop), and fatty acid oxidation (Fgf21, Cpt1a). In vitro, didemnin B decreased THP-1 monocyte proliferation, disrupted THP-1 monocyte-macrophage differentiation, decreased THP-1 macrophage IL-1β secretion, and decreased hepatic stellate cell (HSteC) proliferation and collagen secretion under both basal and lipotoxic (high fatty acid) conditions. Thus, didemnin B improves hepatic steatosis, glucose tolerance, and blood lipids in obesity, in association with moderate, possibly hormetic, upregulation of pathways involved in cell stress response and energy balance in the liver. Furthermore, it decreases the activity of the cell types implicated in liver inflammation and fibrosis in vitro. These findings highlight the therapeutic potential of partial protein synthesis inhibition in the treatment of NAFLD.

Abstract 283: Western Diet Induces Diastolic Dysfunction Linked to Impaired Cardiac Lipid Storage Dynamics That Predate Systolic Dysfunction

Western diet (WD), containing high fat and high refined sugar, is associated with increased risk of cardiovascular disease. However, mechanisms linking WD to cardiomyopathy are far from understood. We hypothesize that WD induces cardiac dysfunction by dysregulation of cardiac lipid dynamics. Adult C57BL/6J mice were fed with either standard chow (CON, fat 4.5 %, sucrose 0%) or western diet (WD, fat 45%, sucrose 21%). At 20 weeks, WD mice exhibited higher body mass, reduced glucose tolerance, and increased isovolumetric relaxation time (IVRT), with no systolic dysfunction vs. CON. However, at 24 weeks, WD caused both systolic and diastolic dysfunction with decreases in left ventricular ejection fraction (66±2% CON vs. 54±2 WD, P &lt;0.05) and fractional shortening (35±2% CON vs. 27±1 WD), with elevated IVRT and E/E’ ratio vs CON. Real time, dynamic-mode 13 C NMR and endpoint LC/MS of isolated perfused hearts supplied 13 C palmitate and 13 C oleate, with unlabeled glucose and lactate, revealed elevated TG content (28% increase vs. CON) with reduced TG turnover in WD hearts (35% decrease vs. CON), concurrent with early diastolic dysfunction at 20 weeks and preceding systolic dysfunction at 24 weeks. WD induced lower content of the TG lipase, ATGL (48% vs. CON), with no change in the TG synthase, DGAT1, suggesting elevated cardiac TG and lower TG turnover are due to reduced TG hydrolysis and not TAG synthesis. Impaired lipid storage dynamics can cause increased generation of potentially lipotoxic acyl intermediates, leading to cardiac dysfunction. The mitochondrial long chain fatty acid transporter, CPT1b was reduced (50%), with no change in the lesser, co-expressed CPT1a isoform in WD hearts. Despite reduced CPT1b in WD hearts, contributions from LCFAs to acetyl CoA production in the citric acid cycle were unchanged, suggesting that the WD provided sufficient LCFAs for mitochondrial oxidation and that the reduced CPT1b was not limiting. In conclusion, western diet expands the TG pool but impairs fat storage dynamics via low ATGL, leading to early diastolic dysfunction and eventual systolic dysfunction. Nutrient overload from WD leads to impaired cardiac lipid dynamics with early diastolic dysfunction that is distinguished from HFpEF due to later systolic dysfunction.

Walnuts and Vegetable Oils Containing Oleic Acid Differentially Affect the Gut Microbiota and Associations with Cardiovascular Risk Factors: Follow-up of a Randomized, Controlled, Feeding Trial in Adults at Risk for Cardiovascular Disease

ABSTRACTBackgroundIt is unclear whether the favorable effects of walnuts on the gut microbiota are attributable to the fatty acids, including α-linolenic acid (ALA), and/or the bioactive compounds and fiber.ObjectiveThis study examined between-diet gut bacterial differences in individuals at increased cardiovascular risk following diets that replace SFAs with walnuts or vegetable oils.MethodsForty-two adults at cardiovascular risk were included in a randomized, crossover, controlled-feeding trial that provided a 2-wk standard Western diet (SWD) run-in and three 6-wk isocaloric study diets: a diet containing whole walnuts (WD; 57–99 g/d walnuts; 2.7% ALA), a fatty acid–matched diet devoid of walnuts (walnut fatty acid–matched diet; WFMD; 2.6% ALA), and a diet replacing ALA with oleic acid without walnuts (oleic acid replaces ALA diet; ORAD; 0.4% ALA). Fecal samples were collected following the run-in and study diets to assess gut microbiota with 16S rRNA sequencing and Qiime2 for amplicon sequence variant picking.ResultsSubjects had elevated BMI (30 ± 1 kg/m2), blood pressure (121 ± 2/77 ± 1 mmHg), and LDL cholesterol (120 ± 5 mg/dL). Following the WD, Roseburia [relative abundance (RA) = 4.2%, linear discriminant analysis (LDA) = 4], Eubacterium eligensgroup (RA = 1.4%, LDA = 4), LachnospiraceaeUCG001 (RA = 1.2%, LDA = 3.2), Lachnospiraceae UCG004 (RA = 1.0%, LDA = 3), and Leuconostocaceae (RA = 0.03%, LDA = 2.8) were most abundant relative to taxa in the SWD (P ≤ 0.05 for all). The WD was also enriched in Gordonibacter relative to the WFMD. Roseburia (3.6%, LDA = 4) and Eubacterium eligensgroup (RA = 1.5%, LDA = 3.4) were abundant following the WFMD, and Clostridialesvadin BB60group (RA = 0.3%, LDA = 2) and gutmetagenome (RA = 0.2%, LDA = 2) were most abundant following the ORAD relative to the SWD (P ≤ 0.05 for all). Lachnospiraceae were inversely correlated with blood pressure and lipid/lipoprotein measurements following the WD.ConclusionsThe results indicate similar enrichment of Roseburia following the WD and WFMD, which could be explained by the fatty acid composition. Gordonibacter enrichment and the inverse association between Lachnospiraceae and cardiovascular risk factors following the WD suggest that the gut microbiota may contribute to the health benefits of walnut consumption in adults at cardiovascular risk. This trial was registered at clinicaltrials.gov as NCT02210767.