Western Diet Intake Research Articles

The spatial impact of a Western diet in enriching Galectin-1-regulated Rho, ECM, and SASP signaling in a novel MASH-HCC mouse model

BackgroundHepatocellular carcinoma (HCC) arising from metabolic dysfunction-associated steatohepatitis (MASH) presents a significant clinical challenge, particularly given the prevalence of the Western diet (WD). The influence of diet on the tumor microenvironment remains poorly understood. Galectin-1 (Gal-1) is a biomarker for HCC and has a crucial role in liver carcinogenesis. Our previous studies demonstrated that silencing Gal-1 effectively treats mouse HCC. However, the impacts of a WD on Gal-1 signaling on MASH to HCC progression are unknown, and this study addresses these knowledge gaps.MethodsWe developed a novel MASH-HCC mouse model. Using spatial transcriptomics and multiplex immunohistochemistry (IHC), we studied the effects of a WD on the liver and tumor microenvironment. By modulating Gal-1 expression through silencing and overexpression, we explored the location-specific impacts of WD on Gal-1 signaling.ResultsPathways such as Rho signaling, extracellular matrix (ECM) remodeling, and senescence-associated secretory phenotypes (SASP) were prominently activated in WD-induced metabolic dysfunction-associated fatty liver disease (MAFLD) and MASH-HCC, compared to healthy livers controls. Furthermore, Rho GTPase effectors, ECM remodeling, neutrophil degranulation, cellular stress, and cell cycle pathways were consistently enriched in human and mouse MASH-HCC. Spatially, these pathways were enriched in the tumor and tumor margins of mouse MASH-HCC. Additionally, there was a notable increase in CD11c and PD-L1-positive cells from non-tumor tissues to the tumor margin and inside the tumor of MASH-HCC, suggesting compromised immune surveillance due to WD intake. Moreover, MASH-HCC exhibited significant Gal-1 induction in N-Cadherin-positive cells, indicating enhanced epithelial-to-mesenchymal transition (EMT). Modulating Gal-1 expression in MASH-HCC further established its specific roles in regulating Rho signaling and SASP in the tumor margin and non-tumor tissues in MASH-HCC.ConclusionWD intake significantly influences vital cellular processes involved in Gal-1-mediated signaling, including Rho signaling and ECM remodeling, in the tumor microenvironment, thereby contributing to the development of MASH-HCC.

Assessing the impact of concurrent high-fructose and high-saturated fat diets on pediatric metabolic syndrome: A review.

High-saturated fat (HF) or high-fructose (HFr) consumption in children predispose them to metabolic syndrome (MetS). In rodent models of MetS, diets containing individually HF or HFr lead to a variable degree of MetS. Nevertheless, simultaneous intake of HF plus HFr have synergistic effects, worsening MetS outcomes. In children, the effects of HF or HFr intake usually have been addressed individually. Therefore, we have reviewed the outcomes of HF or HFr diets in children, and we compare them with the effects reported in rodents. In humans, HFr intake causes increased lipogenesis, hypertriglyceridemia, obesity and insulin resistance. On the other hand, HF diets promote low grade-inflammation, obesity, insulin resistance. Despite the deleterious effects of simultaneous HF plus HFr intake on MetS development in rodents, there is little information about the combined effects of HF plus HFr intake in children. The aim of this review is to warn about this issue, as individually addressing the effects produced by HF or HFr may underestimate the severity of the outcomes of Western diet intake in the pediatric population. We consider that this is an alarming issue that needs to be assessed, as the simultaneous intake of HF plus HFr is common on fast food menus.

Novel Role of Endothelial CD47 in the Regulation of Pathogenesis of Coronary Artery Disease

Background: The anti-phagocytic molecule CD47 is upregulated in atherosclerotic plaques of patients with CVD. However, the role of endothelial cell-specific expression of CD47 in the pathogenesis and progression of atherosclerosis has not yet been fully defined. Kojima et.al. described atheroprotective effect of anti-CD47 antibody by enhancing efferocytosis in atherosclerosis. In this study, we determined whether endothelial cell-specific CD47 regulates efferocytosis in atherosclerosis. Methods: Endothelial cell-specific, tamoxifen-inducible CD47knockout (CD47iECKO) mice were injected with a single dose of AAV-mutant PCSK9 via the tail vein. Susceptibility to atherosclerosis was evaluated in cross sections of the aortic sinus in mice fed Western Diet for 12 weeks. Using single-cell RNA sequencing and in vitro efferocytosis assays, we investigated the role of CD47 in regulating efferocytosis in an atherosclerotic mouse model. Results: Endothelial cell-specific deletion of CD47 led to a significant plaque reduction in the aortic sinus of athero-CD47iECKO mice. Cluster analysis and gene expression profiles of 20,000 aortic endothelial cells from athero-control and athero-CD47iECKO mice identified 10 major cell types from the integrated data: endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells (B cells, T cells, macrophage), erythrocytes, oligodendrocytes cells, Schwann cells, and pericytes. After Western Diet intake, in the CD47iECKO group, a subpopulation of endothelial cells as well as fibroblasts, T-cells, B-cells, resident aortic macrophages, erythrocytes, oligodendrocytes, and pericytes were increased, while vascular smooth muscle cell numbers decreased. Using an in vitro efferocytosis assay on isolated primary endothelial cells from control and CD47iECKO mice, we observed CD47 deletion induced engulfment of apoptotic Jurkat cells, which had been exposed to BAY11-7082 (NF-κB inhibitor) to stimulate the apoptotic attributes. Quantitative PCR analyses showed that CD47 deletion increases the expression of efferocytosis receptor FasL, CX3CL1, Gpr132, MerTK, Scarb1, Sirpa, TSP1, and HMGB1. Conclusion: Our study indicates that genetic deletion of CD47 in endothelial cells attenuates atheroma progression by enhancing efferocytosis. This study also reveals phenotypic heterogenicity of endothelial cells at the single cell level during atherogenesis and provides a deeper understanding of endothelial cell biology in atherosclerosis that may facilitate the development of novel therapeutic interventions for this cardiovascular disease. NIH, AHA. 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.

Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling

Western diet (WD) consumption during early life developmental periods is associated with impaired memory function, particularly for hippocampus (HPC)-dependent processes. We developed an early life WD rodent model associated with long-lasting HPC dysfunction to investigate the neurobiological mechanisms mediating these effects. Rats received either a cafeteria-style WD (ad libitum access to various high-fat/high-sugar foods; CAF) or standard healthy chow (CTL) during the juvenile and adolescent stages (postnatal days 26–56). Behavioral and metabolic assessments were performed both before and after a healthy diet intervention period beginning at early adulthood. Results revealed HPC-dependent contextual episodic memory impairments in CAF rats that persisted despite the healthy diet intervention. Given that dysregulated HPC acetylcholine (ACh) signaling is associated with memory impairments in humans and animal models, we examined protein markers of ACh tone in the dorsal HPC (HPCd) in CAF and CTL rats. Results revealed significantly lower protein levels of vesicular ACh transporter in the HPCd of CAF vs. CTL rats, indicating chronically reduced ACh tone. Using intensity-based ACh sensing fluorescent reporter (iAChSnFr) in vivo fiber photometry targeting the HPCd, we next revealed that ACh release during object-contextual novelty recognition was highly predictive of memory performance and was disrupted in CAF vs. CTL rats. Neuropharmacological results showed that alpha 7 nicotinic ACh receptor agonist infusion in the HPCd during training rescued memory deficits in CAF rats. Overall, these findings reveal a functional connection linking early life WD intake with long-lasting dysregulation of HPC ACh signaling, thereby identifying an underlying mechanism for WD-associated memory impairments.

Taste receptor type 1 member 3 regulates Western diet-induced male infertility

Western diet (WD), characterized by a high intake of fats and sugary drinks, is a risk factor for male reproductive impairment. However, the molecular mechanisms underlying this remain unclear. Taste receptor type 1 member 3 (TAS1R3), activated by ligands of WD, is highly expressed in extra-oral tissues, particularly in the testes. Here, we investigated to determine the effects of WD intake on male reproduction and whether TAS1R3 mediates WD-induced impairment in male reproduction. Male C57BL/6 J wild-type (WT) and Tas1r3 knockout (KO) mice were fed either a normal diet and plain water (ND) or a 60 % high-fat-diet and 30 % (w/v) sucrose water (WD) for 18 weeks (n = 7–9/group). Long-term WD consumption significantly impaired sperm count, motility and testicular morphology in WT mice with marked Tas1r3 overexpression, whereas Tas1r3 KO mice were protected from WD-induced reproductive impairment. Testicular transcriptome analysis revealed downregulated AMP-activated protein kinase (AMPK) signaling and significantly elevated AMPK-targeted nuclear receptor 4A1 (Nr4a1) expression in WD-fed Tas1r3 KO mice. In vitro studies further validated that Tas1r3 knockdown in Leydig cells prevented the suppression of Nr4a1 and downstream steroidogenic genes (Star, Cyp11a1, Cyp17a1, and Hsd3b1) caused by high glucose, fructose, and palmitic acid levels, and maintained the levels of testosterone. Additionally, we analyzed the public human dataset to assess the clinical implications of our findings and confirmed a significant association between TAS1R3 and male-infertility-related diseases. Our findings suggest that TAS1R3 regulates WD-induced male reproductive impairment via the AMPK/NR4A1 signaling and can be a novel therapeutic target for male infertility.

Probiotic and Muscadine Grape Extract Interventions Shift the Gut Microbiome and Improve Metabolic Parameters in Female C57BL/6 Mice.

Obesity and Western-like diet consumption leads to gut microbiome dysbiosis, which is associated with the development of cardio-metabolic diseases and poor health outcomes. The objective of this study was to reduce Western diet-mediated gut microbial dysbiosis, metabolic dysfunction, and systemic inflammation through the administration of a novel combined intervention strategy (oral probiotic bacteria supplements and muscadine grape extract (MGE)). To do so, adult female C57BL/6 mice were fed a low-fat control or Western-style diet and sub-grouped into diet alone, probiotic intervention, antibiotic treatments, MGE supplementation, a combination of MGE and probiotics, or MGE and antibiotics for 13 weeks. Mouse body weight, visceral adipose tissue (VAT), liver, and mammary glands (MG) were weighed at the end of the study. Fecal 16S rRNA sequencing was performed to determine gut bacterial microbiome populations. Collagen, macrophage, and monocyte chemoattractant protein-1 (MCP-1) in the VAT and MG tissue were examined by immunohistochemistry. Adipocyte diameter was measured in VAT. Immunohistochemistry of intestinal segments was used to examine villi length, muscularis thickness, and goblet cell numbers. We show that dietary interventions in Western diet-fed mice modulated % body weight gain, visceral adiposity, MG weight, gut microbial populations, and inflammation. Intervention strategies in both diets effectively reduced VAT and MG fibrosis, VAT and MG macrophages, adipocyte diameter, and VAT and MG MCP-1. Interventions also improved intestinal health parameters. In conclusion, dietary intervention with MGE and probiotics modulates several microbial, inflammatory, and metabolic factors reducing poor health outcomes associated with Western diet intake.

Taste receptor type 1 member 3 enables western diet-induced anxiety in mice

BackgroundAccumulating evidence supports that the Western diet (WD), a diet high in saturated fat and sugary drinks, contributes to the pathogenesis of anxiety disorders, which are the most prevalent mental disorders worldwide. However, the underlying mechanisms by which WD causes anxiety remain unclear. Abundant expression of taste receptor type 1 member 3 (TAS1R3) has been identified in the hypothalamus, a key brain area involved in sensing peripheral nutritional signals and regulating anxiety. Thus, we investigated the influence of excessive WD intake on anxiety and mechanisms by which WD intake affects anxiety development using wild-type (WT) and Tas1r3 deficient (Tas1r3−/−) mice fed a normal diet (ND) or WD for 12 weeks.ResultsWD increased anxiety in male WT mice, whereas male Tas1r3−/− mice were protected from WD-induced anxiety, as assessed by open field (OF), elevated plus maze (EPM), light–dark box (LDB), and novelty-suppressed feeding (NSF) tests. Analyzing the hypothalamic transcriptome of WD-fed WT and Tas1r3−/− mice, we found 1,432 genes significantly up- or down-regulated as a result of Tas1r3 deficiency. Furthermore, bioinformatic analysis revealed that the CREB/BDNF signaling-mediated maintenance of neuronal regeneration, which can prevent anxiety development, was enhanced in WD-fed Tas1r3−/− mice compared with WD-fed WT mice. Additionally, in vitro studies further confirmed that Tas1r3 knockdown prevents the suppression of Creb1 and of CREB-mediated BDNF expression caused by high levels of glucose, fructose, and palmitic acid in hypothalamic neuronal cells.ConclusionsOur results imply that TAS1R3 may play a key role in WD-induced alterations in hypothalamic functions, and that inhibition of TAS1R3 overactivation in the hypothalamus could offer therapeutic targets to alleviate the effects of WD on anxiety.

A mixture of glyphosate and 2,4-D herbicides enhances the deleterious reproductive outcomes induced by Western diet in obese male mice.

The consumption of Western diet (WD) - enriched in fats and sugars - is associated with overweight, obesity and male reproductive disorders. In addition to WD intake, crops and dairy products display residues of herbicides, including glyphosate and 2,4-D that are widely applied worldwide. The concomitant exposure to WD and herbicides - mimicking contemporary scenarios - is not fully investigated. Thus, we evaluated the effects of glyphosate and 2,4-D, alone or in mixture, on WD-induced alterations in the male genital system. Male C57BL6J mice were submitted to WD (chow containing 20% lard, 0.2% cholesterol, 20% sucrose, and high sugar solution with 23.1 and 18.9 g/L of D-fructose and D-glucose) for 6 months. Concomitantly to WD, the animals received glyphosate (0.05, 5, or 50 mg/kg/day), 2,4-D (0.02, 2 or 20 mg/kg/day) or their mixture (0, 05 + 0.02, 5 + 2, or 50 + 20 mg/kg/day) by intragastrical administration (5×/week). Doses were based on Acceptable Daily Intake (ADIs) or No Observed Adverse Effect Level (NOAEL) values. Herbicide exposure did not alter the WD-induced obesity, hypercholesterolemia and hyperglycemia. WD induced sperm cell abnormalities, reduced the number, volume and area of Leydig cells, enhanced the frequency of epididymal abnormalities, decreased the proliferation in both germinal and epididymal epithelia, and reduced the number of androgen receptor (AR) positive epididymal cells. Remarkably, the herbicide mixtures promoted such WD-induced effects: increased the frequency of sperm cell and epididymal abnormalities (absence of sperm, cytoplasmic vacuoles, and clear cell hypertrophy) (5 + 2 and 50 + 20 doses); decreased Leydig cell nuclei volume and area (5 + 2 and 50 + 20 doses), reduced epididymal cell proliferation (all mixtures), and AR expression (50 + 20 dose). In addition, herbicide mixtures reduced serum testosterone levels (5 + 2 and 50 + 20 doses). Our findings indicate that the mixture of glyphosate and 2,4-D herbicides, mimicking environmentally relevant scenarios, promotes WD-induced changes in the male genital system.

Uncovering the Gut-Liver Axis Biomarkers for Predicting Metabolic Burden in Mice.

Western diet (WD) intake, aging, and inactivation of farnesoid X receptor (FXR) are risk factors for metabolic and chronic inflammation-related health issues ranging from metabolic dysfunction-associated steatotic liver disease (MASLD) to dementia. The progression of MASLD can be escalated when those risks are combined. Inactivation of FXR, the receptor for bile acid (BA), is cancer prone in both humans and mice. The current study used multi-omics including hepatic transcripts, liver, serum, and urine metabolites, hepatic BAs, as well as gut microbiota from mouse models to classify those risks using machine learning. A linear support vector machine with K-fold cross-validation was used for classification and feature selection. We have identified that increased urine sucrose alone achieved 91% accuracy in predicting WD intake. Hepatic lithocholic acid and serum pyruvate had 100% and 95% accuracy, respectively, to classify age. Urine metabolites (decreased creatinine and taurine as well as increased succinate) or increased gut bacteria (Dorea, Dehalobacterium, and Oscillospira) could predict FXR deactivation with greater than 90% accuracy. Human disease relevance is partly revealed using the metabolite-disease interaction network. Transcriptomics data were also compared with the human liver disease datasets. WD-reduced hepatic Cyp39a1 (cytochrome P450 family 39 subfamily a member 1) and increased Gramd1b (GRAM domain containing 1B) were also changed in human liver cancer and metabolic liver disease, respectively. Together, our data contribute to the identification of noninvasive biomarkers within the gut-liver axis to predict metabolic status.

2,4-dichlorophenoxyacetic acid (2,4-D) exposure during postnatal development alters the effects of western diet on mouse prostate

Western diet (WD), abundant in saturated fats and simple carbohydrates, has been associated with the development of prostate diseases. In addition, 2,4-dichlorophenoxyacetic acid (2,4-D), an herbicide used in agricultural and non-agricultural settings, may interfere with the endocrine system impacting reproductive health. The association of both factors is something common in everyday life, however, there are no relevant studies associating them as possible modulators of prostatic diseases. This study evaluated the action of the herbicide 2,4-D on the postnatal development of the prostate in mice fed with WD. Male C57Bl/6J mice received simultaneously a WD and 2,4-D at doses of 0.02, 2.0, or 20.0 mg/kg b.w./day for 6 months. The prolongated WD intake induced obesity and glucose intolerance, increasing body weight and fat. WD induced morphological changes and increased PCNA-positive epithelial cells in prostate. Additionally, the WD increased gene expression of AR, antioxidant targets, inflammation-related cytokines, cell repair and turnover, and targets related to methylation and miRNAs biosynthesis compared to the counterpart (basal diet). 2,4-D (0.02 and 2.0) changed prostate morphology and gene expression evoked by WD. In contrast, the WD group exposed to 20 mg/kg of 2,4-D reduced feed intake and body weight, and increased expression of androgen receptor and genes related to cell repair and DNA methylation compared to the negative control. Our results showed that 2,4-D was able to modulate the effects caused by WD, mainly at lower doses. However, further studies are needed to elucidate the mechanisms of 2,4-D on the obesogenic environment caused by the WD.

Gut taste receptor type 1 member 3 is an intrinsic regulator of Western diet-induced intestinal inflammation

BackgroundLong-term intake of a Western diet (WD), characterized by a high-fat content and sugary drinks, is hypothesized to contribute to the development of inflammatory bowel disease (IBD). Despite the identified clinical association, the molecular mechanisms by which dietary changes contribute to IBD development remain unknown. Therefore, we examined the influence of long-term intake of a WD on intestinal inflammation and the mechanisms by which WD intake affects IBD development.MethodsMice fed normal diet or WD for 10 weeks, and bowel inflammation was evaluated through pathohistological and infiltrated inflammatory cell assessments. To understand the role of intestinal taste receptor type 1 member 3 (TAS1R3) in WD-induced intestinal inflammation, cultured enteroendocrine cells harboring TAS1R3, subjected to RNA interference or antagonist treatment, and Tas1r3-deficient mice were used. RNA-sequencing, flow cytometry, 16S metagenomic sequencing, and bioinformatics analyses were performed to examine the involved mechanisms. To demonstrate their clinical relevance, intestinal biopsies from patients with IBD and mice with dextran sulfate sodium-induced colitis were analyzed.ResultsOur study revealed for the first time that intestinal TAS1R3 is a critical mediator of WD-induced intestinal inflammation. WD-fed mice showed marked TAS1R3 overexpression with hallmarks of serious bowel inflammation. Conversely, mice lacking TAS1R3 failed to exhibit inflammatory responses to WD. Mechanistically, intestinal transcriptome analysis revealed that Tas1r3 deficiency suppressed mTOR signaling, significantly increasing the expression of PPARγ (a major mucosal defense enhancer) and upregulating the expression of PPARγ target-gene (tight junction protein and antimicrobial peptide). The gut microbiota of Tas1r3-deficient mice showed expansion of butyrate-producing Clostridia. Moreover, an increased expression of host PPARγ-signaling pathway proteins was positively correlated with butyrate-producing microbes, suggesting that intestinal TAS1R3 regulates the relationship between host metabolism and gut microflora in response to dietary factors. In cultured intestinal cells, regulation of the TAS1R3–mTOR–PPARγ axis was critical for triggering an inflammatory response via proinflammatory cytokine production and secretion. Abnormal regulation of the axis was observed in patients with IBD.ConclusionsOur findings suggest that the TAS1R3–mTOR–PPARγ axis in the gut links Western diet consumption with intestinal inflammation and is a potential therapeutic target for IBD.

The essential roles of FXR in diet and age influenced metabolic changes and liver disease development: a multi-omics study

BackgroundAging and diet are risks for metabolic diseases. Bile acid receptor farnesoid X receptor (FXR) knockout (KO) mice develop metabolic liver diseases that progress into cancer as they age, which is accelerated by Western diet (WD) intake. The current study uncovers the molecular signatures for diet and age-linked metabolic liver disease development in an FXR-dependent manner.MethodsWild-type (WT) and FXR KO male mice, either on a healthy control diet (CD) or a WD, were euthanized at the ages of 5, 10, or 15 months. Hepatic transcriptomics, liver, serum, and urine metabolomics as well as microbiota were profiled.ResultsWD intake facilitated hepatic aging in WT mice. In an FXR-dependent manner, increased inflammation and reduced oxidative phosphorylation were the primary pathways affected by WD and aging. FXR has a role in modulating inflammation and B cell-mediated humoral immunity which was enhanced by aging. Moreover, FXR dictated neuron differentiation, muscle contraction, and cytoskeleton organization in addition to metabolism. There were 654 transcripts commonly altered by diets, ages, and FXR KO, and 76 of them were differentially expressed in human hepatocellular carcinoma (HCC) and healthy livers. Urine metabolites differentiated dietary effects in both genotypes, and serum metabolites clearly separated ages irrespective of diets. Aging and FXR KO commonly affected amino acid metabolism and TCA cycle. Moreover, FXR is essential for colonization of age-related gut microbes. Integrated analyses uncovered metabolites and bacteria linked with hepatic transcripts affected by WD intake, aging, and FXR KO as well as related to HCC patient survival.ConclusionFXR is a target to prevent diet or age-associated metabolic disease. The uncovered metabolites and microbes can be diagnostic markers for metabolic disease.

High Dietary Iron in Western Diet-Fed Male Rats Causes Pancreatic Islet Injury and Acute Pancreatitis

BackgroundHigh dietary iron has been linked to an increased type 2 diabetes risk. We have previously shown that intrauterine growth restriction (IUGR) and feeding a Western diet (WD) to male Sprague-Dawley rats independently, as well as together, cause pancreatic islet inflammation, fibrosis, and hemosiderosis. ObjectivesTo investigate whether iron has a role in the pathogenesis of this inflammatory islet injury caused by IUGR and WD intake. MethodsMale Sprague-Dawley offspring of bilateral uterine artery ligated (IUGR) and sham-operated (Sham) dams, fostered to nonoperated dams, were fed a WD [45% sucrose, 19.4% protein and 23% fat (w/w)] containing low iron (LI, 20 mg/kg) or high iron (HI, 500 mg/kg) from weaning. Four groups were studied: Sham-LI, Sham-HI, IUGR-LI, and IUGR-HI. Serial measurements of rat body weight, blood glucose, lipids and insulin, an intraperitoneal glucose tolerance test (age 13 wk), and histological analysis of pancreas and liver (age 14 wk) were recorded. The effects of iron, IUGR, and their interaction, on these measurements have been analyzed. ResultsWD with HI compared with LI caused an 11% greater weight gain by age 14 wk (P < 0.001), impaired glucose tolerance [AUC for glucose (G-AUC) 17% higher; P < 0.001), acute pancreatitis (17/18, HI; 6/17, LI; P < 0.001), pancreas-associated fat necrosis and saponification (7/18, HI; 0/17 LI; P < 0.01), and a trend to islet fibrotic injury (7/18, HI; 1/17 LI; P = 0.051). Although pancreatic and hepatic steatosis was evident in almost all WD-fed rats, pancreatic and hepatic iron accumulation was prevalent only in HI-fed rats (P < 0.0001 for both), being only mild in the livers. IUGR, independent of dietary iron, also caused impairment in glucose tolerance (G-AUC: 17% higher; P < 0.05). ConclusionsA postweaning WD containing HI, independent of IUGR, causes acute pancreatitis and islet injury in Sprague-Dawley rats suggesting a role of dietary iron in the development of steatopancreatitis.

Activation of TRPV1 improves natriuresis and salt sensitivity in high-fat diet fed mice

Western diet (WD) intake increases morbidity of obesity and salt-sensitive hypertension albeit mechanisms are largely unknown. We investigated the role of transient receptor potential vanilloid 1 (TRPV1) in WD intake-induced hypertension. TRPV1−/− and wild-type (WT) mice were fed a normal (CON) or Western diet (WD) for 16–18 weeks. Mean arterial pressure (MAP) after normal sodium glucose (NSG) loading with or without L-NAME (a NO synthase inhibitor) or N-oleoyldopamine (OLDA, a TRPV1agonist) was not different between the two strains on CON.WT or TRPV1−/− mice fed WD had increased MAP after NSG, with a greater magnitude in TRPV1−/− mice. OLDA decreased while L-NAME increased MAP in WT-WD but not in TRPV1−/−-WD mice. The urinary nitrates plus nitrites excretion (UNOx), an indicator of renal NO production, was increased in both strains on CON after NSG. TRPV1 ablation with WD intake abolished NSG-induced increment in UNOx. OLDA further increased while L-NAME prevented NSG-induced increment in UNOx in WT-WD mice. Urinary sodium excretion was increased in both strains on CON and in WT-WD mice but not in TRPV1−/−-WD mice after NSG. OLDA further increased while L-NAME prevented NSG-induced increases in sodium excretion in WT-WD but not in TRPV1−/−-WD mice. Thus, TRPV1 ablation increases salt sensitivity during WD intake possibly via impaired renal NO production and sodium excretion. Activation of TRPV1 enhances renal NO production and sodium excretion, resulting in prevention of increased salt sensitivity during WD intake.

Intestinal Microbiota Remodeling Protects Mice from Western Diet-Induced Brain Inflammation and Cognitive Decline.

It has been shown that the Western diet (WD) induces systemic inflammation and cognitive decline. Moreover, probiotic supplementation and antibiotic treatment reduce diet-induced hepatic inflammation. The current study examines whether shaping the gut microbes by Bifidobacterium infantis (B. infantis) supplementation and antibiotic treatment reduce diet-induced brain inflammation and improve neuroplasticity. Furthermore, the significance of bile acid (BA) signaling in regulating brain inflammation was studied. Mice were fed a control diet (CD) or WD for seven months. B. infantis was supplemented to WD-fed mice to study brain inflammation, lipid, metabolomes, and neuroplasticity measured by long-term potentiation (LTP). Broad-spectrum coverage antibiotics and cholestyramine treatments were performed to study the impact of WD-associated gut microbes and BA in brain inflammation. Probiotic B. infantis supplementation inhibited diet-induced brain inflammation by reducing IL6, TNFα, and CD11b levels. B. infantis improved LTP and increased brain PSD95 and BDNF levels, which were reduced due to WD intake. Additionally, B. infantis reduced cecal cholesterol, brain ceramide and enhanced saturated fatty acids. Moreover, antibiotic treatment, as well as cholestyramine, diminished WD-induced brain inflammatory signaling. Our findings support the theory that intestinal microbiota remodeling by B. infantis reduces brain inflammation, activates BA receptor signaling, and improves neuroplasticity.

Western Diet and Psoriatic-Like Skin and Joint Diseases: A Potential Role for the Gut Microbiota

Shi etal. (2021) in "Short-term Western diet intake promotes IL-23-mediated skin and joint inflammation accompanied by changes to the gut microbiota in mice" show that Western diet (WD) exacerbates an IL-23 minicircle‒mediated model of psoriasis and psoriatic arthritis, with an expansion of IL-17A‒expressing γδ T cells and shifts to the gut microbial community. WD-associated inflammation is mitigated by diet manipulation or antibiotic administration. These results suggest that dietary manipulation may be useful in the treatment of IL-23‒mediated disease, possibly through the modulation of the gut microbiota.

Short-Term Western Diet Intake Promotes IL-23‒Mediated Skin and Joint Inflammation Accompanied by Changes to the Gut Microbiota in Mice

We previously showed that exposure to a high-sugar and moderate-fat diet (i.e., Western diet [WD]) in mice induces appreciable skin inflammation and enhances the susceptibility to imiquimod-induced psoriasiform dermatitis, suggesting that dietary components may render the skin susceptible to psoriatic inflammation. In this study, utilizing an IL-23 minicircle-based model with features of both psoriasiform dermatitis and psoriatic arthritis, we showed that intake of WD for 10 weeks predisposed mice not only to skin but also to joint inflammation. Both WD-induced skin and joint injuries were associated with an expansion of IL-17A‒producing γδ T cells and increased expression of T helper type 17 cytokines. After IL-23 minicircle delivery, WD-fed mice had reduced microbial diversity and pronounced dysbiosis. Treatment with broad-spectrum antibiotics suppressed IL-23‒mediated skin and joint inflammation in the WD-fed mice. Strikingly, reduced skin and joint inflammation with a partial reversion of the gut microbiota were noted when mice switched from a WD to a standard diet after IL-23 minicircle delivery. These findings reveal that a short-term WD intake‒induced dysbiosis is accompanied by enhanced psoriasis-like skin and joint inflammation. Modifications toward a healthier dietary pattern should be considered in patients with psoriatic skin and/or joint disease.

Long-term Western diet intake leads to dysregulated bile acid signaling and dermatitis with Th2 and Th17 pathway features in mice

BackgroundDietary interventions are implicated in the development of atopic dermatitis, psoriasis, and acne. ObjectiveTo investigate the effect of diet and the bile acid (BA) receptors, such as TGR5 (Takeda G protein receptor 5) and S1PR2 (sphingosine-1-phosphate receptor 2) in the development of dermatitis. MethodsC57BL/6 mice were fed a control diet (CD) or Western diet (WD) since weaning until they were 10 months old followed by analyzing histology, gene expression, and BA profiling. ResultsMice developed dermatitis as they aged and the incidence was higher in females than males. Additionally, WD intake substantially increased the incidence of dermatitis. Cutaneous antimicrobial peptide genesS100A8, S100A9, and Defb4 were reduced in WD-fed mice, but increased when mice developed skin lesions. In addition, Tgr5 and TGR5-regulated Dio2 and Nos3 were reduced in WD intake but induced in dermatitic lesions. Trpa1 and Trpv1, which mediate itch, were also increased in dermatitic lesions. The expression of S1pr2 and genes encoding sphingosine kinases, S1P phosphatases, binding protein, and transporter were all reduced by WD intake but elevated in dermatitic lesions. Furthermore, dermatitis development increased total cutaneous BA with an altered profile, which may change TGR5 and S1PR2 activity. Moreover, supplementation with BA sequestrant cholestyramine reduced epidermal thickening as well as cutaneous inflammatory cytokines. ConclusionIn summary, activation of TGR5 and S1PR2, which regulate itch, keratinocyte proliferation, metabolism, and inflammation, may contribute to WD-exacerbated dermatitis with Th2 and Th17 features. In addition, elevated total BA play a significant role in inducing dermatitis and cutaneous inflammation.

Ablation of TRPV1 Elevates Nocturnal Blood Pressure in Western Diet-fed Mice

Background: This study tested the hypothesis that genetically ablation of transient receptor potential vanilloid type 1 (TRPV1) exacerbates impairment of baroreflex in mice fed a western diet (WD) and leads to distinct diurnal and nocturnal blood pressure patterns.Methods: TRPV1 gene knockout (TRPV1-/-) and wild-type (WT) mice were given a WD or normal diet (CON) for 4 months.Results: Capsaicin, a selective TRPV1 agonist, increased ipsilateral afferent renal nerve activity in WT but not TRPV1-/- mice. The sensitivity of renal sympathetic nerve activity and heart rate responses to baroreflex were reduced in TRPV1-/--CON and WT-WD and further decreased in TRPV1-/--WD compared to the WT-CON group. Urinary norepinephrine and serum insulin and leptin at day and night were increased in WT-WD and TRPV1-/--WD, with further elevation at night in TRPV1-/--WD. WD intake increased leptin, IL-6, and TNF-α in adipose tissue, and TNF-α antagonist III, R-7050, decreased leptin in TRPV1-/--WD. The urinary albumin level was higher in TRPV1-/--WD than WT-WD. Blood pressure was not dif-ferent during daytime among all groups, but increased at night in the TRPV1-/--WD group compared with other groups.Conclusions: TRPV1 ablation leads to elevated nocturnal but not diurnal blood pressure, which is probably attributed to fur-ther enhancement of sympathetic drives at night.

TRPV1 protects renal ischemia-reperfusion injury in diet-induced obese mice by enhancing CGRP release and increasing renal blood flow.

BackgroundObesity is a major risk factor for end-stage renal disease. Using transient receptor potential vanilloid 1 knockout (TRPV1−/−) mice, we tested the hypothesis that TRPV1 protects against obesity-induced exacerbation of renal ischemia-reperfusion (I/R) injury.MethodsTRPV1−/− and wild-type (WT) mice were fed a chow or Western diet (WD) for 22–23 weeks. After that, mice were subjected to renal I/R injury, and renal cortical blood flow (CBF) and medullary blood flow (MBF) were measured.ResultsThe Western diet significantly increased body weight and fasting blood glucose levels in both TRPV1−/− and WT mice. WD-induced impairment of glucose tolerance was worsened in TRPV1−/− mice compared with WT mice. WD intake prolonged the time required to reach peak reperfusion in the cortex and medulla (both P < 0.05), decreased the recovery rate of CBF (P < 0.05) and MBF (P < 0.05), and increased blood urea nitrogen, plasma creatinine, and urinary 8-isoprostane levels after I/R in both mouse strains, with greater effects in TRPV1−/− mice (all P < 0.05). Renal I/R increased calcitonin gene-related peptide (CGRP) release in WT but not in TRPV1−/− mice, and WD attenuated CGRP release in WT mice. Moreover, blockade of CGRP receptors impaired renal regional blood flow and renal function in renal I/R injured WT mice.ConclusionThese results indicate that TRPV1 plays a protective role in WD-induced exacerbation of renal I/R injury probably through enhancing CGRP release and increasing renal blood flow.