Western Diet Research Articles

High chloride induces aldosterone resistance in the distal nephron.

Increasing the dietary intake of K+ in the setting of a high salt intake promotes renal Na+ excretion even though K+ concurrently enhances the secretion of aldosterone, the most effective stimulus for renal Na+ reabsorption. Here, we questioned whether in the high salt state a mechanism exists, which attenuates the aldosterone response to prevent renal Na+ reabsorption after high K+ intake. Mice were fed diets containing varying amounts of Na+ combined with KCl or KCitrate. Murine cortical connecting duct (mCCDcl1) cells were cultured in media containing normal or high [Cl-]. The response to aldosterone was analyzed by high-resolution imaging and by biochemical approaches. The canonical cellular response to aldosterone, encompassing translocation of the mineralocorticoid receptor (MR) and activation of the epithelial Na+ channel ENaC was repressed in Na+-replete mice fed a high KCl diet, even though plasma aldosterone concentrations were increased. The response to aldosterone was restored in Na+-replete mice when the extracellular [Cl-] increase was prevented by feeding a high KCitrate diet. In mCCDcl1 cells, an elevated extracellular [Cl-] was sufficient to disrupt the aldosterone-induced MR translocation. These findings indicate a pivotal role for extracellular [Cl-] in modulating renal aldosterone signaling to adapt MR activation by a high K+ intake to the NaCl balance. An impairment of [Cl-]-mediated aldosterone resistance may contribute to excessive MR activation by aldosterone in the presence of a high salt intake characteristic of the Western diet, resulting in an inappropriate salt reabsorption and its downstream detrimental effects.

Yeast β-glucan supplementation lowers insulin resistance without altering microbiota composition compared to placebo in subjects with Type II diabetes: a phase I exploratory study.

The increased global prevalence of type II diabetes mellitus (T2DM) is associated with consumption of low fibre "Western diets". Characteristic metabolic parameters of these individuals include insulin resistance, high fasting and postprandial glucose, as well as low-grade systemic inflammation. Gut microbiota composition is altered significantly in these cohorts suggesting a causative link between diet, microbiota and disease. Dietary fibre consumption has been shown to alleviate these changes and improve glucose parameters in individuals with metabolic disease. We previously reported that yeast β-glucan (yeast beta-1,3/1,6-D-glucan; Wellmune) supplementation ameliorated hyperinsulinemia and insulin resistance in a murine model. Here we conducted a randomised, placebo-controlled, two-armed dietary fibre phase I exploratory intervention study in patients with T2DM. The primary outcome measure was alteration to microbiota composition while the secondary outcome measures included markers of glycaemic control, inflammation as well as metabolomics. Patients were supplemented with 2.5g/day of maltodextrin (placebo) or yeast β-1,3/1,6-D-glucan (treatment). Yeast β-glucan (Wellmune) lowered insulin resistance (HOMA-IR) compared to the placebo maltodextrin after 8 weeks of consumption. TNFα was significantly lower after 4 weeks of β-glucan supplementation. Significantly higher faecal concentrations of several bile acids were detected in the treatment group when compared to the placebo after 8 weeks. These included tauroursodeoxycholic acid (TUDCA) which was previously shown to improve glucose control and lower insulin resistance. Interestingly, the hypoglycaemic and anti-inflammatory effect of yeast β-glucan was independent of any changes in faecal microbiota composition or short-chain fatty acid (SCFA) levels. Our findings highlight the potential of yeast β-glucan to lower insulin resistance in patients with T2DM.

In vivo manipulation of human gut Bacteroides fitness by abiotic oligosaccharides.

Synthetic glycans (SGs) containing glycosidic linkages and structures not identified in nature offer a means for deliberately altering microbial community properties. Here pools of SG oligosaccharides were generated via polymerization of monosaccharides and screened for their ability to increase saccharolytic Bacteroides in ex vivo cultures of human fecal samples. A lead SG preparation was orally administered to gnotobiotic mice harboring a consortium of 56 cultured, phylogenetically diverse human gut bacteria and fed a Western diet. The abundances of 3 of 15 Bacteroides strains increased, most prominently B. intestinalis. Underlying mechanisms were characterized by analyzing in vivo expression of the carbohydrate utilization machinery, using retrievable microscopic paramagnetic particles with bound SG oligosaccharides and assaying SG degradation by individual purified B. intestinalis glycoside hydrolases. The results reveal that SGs can selectively co-opt carbohydrate utilization machinery in different human gut Bacteroides and demonstrate a means for identifying artificial carbohydrate structures for targeted bacterial manipulation.

A novel model of cardiovascular–kidney–metabolic syndrome combining unilateral nephrectomy and high-salt–sugar–fat diet in mice

The aim of this study was to explore biological interaction and pathophysiology mechanisms in a new mouse model of cardiovascular–kidney–metabolic (CKM) syndrome, induced by chronic moderate renal failure in combination with consumption of a customized Western diet rich in carbohydrates, fat and salt. Male C57BL/6J mice were subjected to unilateral nephrectomy, fed a customized Western diet rich not only in sugar and fat but also in salt, and followed for 12 weeks or 20 weeks. Sham-operated mice on a standard chow served as healthy controls. Body composition, weight gain, glucose metabolism, fat distribution, blood pressure, cardiac function, vascular reactivity, renal function, inflammation and mitochondrial function were measured and combined with biochemical and histopathological analyses. The novel triple-hit model of CKM syndrome showed signs and symptoms of metabolic syndrome, disturbed glucose metabolism, impaired adipocyte physiology and fat redistribution, cardiovascular dysfunction, renal damage and dysfunction, systemic inflammation, elevated blood pressure and cardiac remodeling. The pathological changes were more pronounced in mice after prolonged exposure for 20 weeks, but no deaths occurred. In the present mouse model of CKM syndrome, profound and significant metabolic, cardiac, vascular and renal dysfunctions and injuries emerged by using a Western diet rich not only in fat and carbohydrates but also in salt. This multisystem disease model could be used for mechanistic studies and the evaluation of new therapeutic strategies.

Targeting Unc5b in macrophages drives atherosclerosis regression and pro-resolving immune cell function

Atherosclerosis results from lipid-driven inflammation of the arterial wall that fails to resolve. Imbalances in macrophage accumulation and function, including diminished migratory capacity and defective efferocytosis, fuel maladaptive inflammation and plaque progression. The neuroimmune guidance cue netrin-1 has dichotomous roles in inflammation partly due to its multiple receptors; in atherosclerosis, netrin-1 promotes macrophage survival and retention via its receptor Unc5b. To minimize the pleiotropic effects of targeting netrin-1, we tested the therapeutic potential of deleting Unc5b in mice with advanced atherosclerosis. We generated Unc5bfl/flCx3cr1creERT2/WT mice, which allowed conditional deletion of Un5b (∆Unc5bMØ) in monocytes and macrophages by tamoxifen injection. After inducing advanced atherosclerosis by hepatic PCSK9 overexpression and western diet feeding for 20 wk, Unc5b was deleted and hypercholesterolemia was normalized to simulate clinical lipid management. Deletion of myeloid Unc5b led to a 40% decrease in atherosclerotic plaque burden and reduced plaque complexity compared to Unc5bfl/flCx3cr1WT/WT littermate controls (CtrlMØ). Consistently, plaque macrophage content was reduced by 50% in ∆Unc5bMØ mice due to reduced plaque Ly6Chi monocyte recruitment and macrophage retention. Compared to CtrlMØ mice, plaques in ∆Unc5bMØ mice had reduced necrotic area and fewer apoptotic cells, which correlated with improved efferocytotic capacity by Unc5b-deficient macrophages in vivo and in vitro. Beneficial changes in macrophage dynamics in the plaque upon Unc5b deletion were accompanied by an increase in atheroprotective T cell populations, including T-regulatory and Th2 cells. Our data identify Unc5b in advanced atherosclerosis as a therapeutic target to induce pro-resolving restructuring of the plaque immune cells and to promote atherosclerosis regression.

Decompensated MASH-Cirrhosis Model by Acute and Toxic Effects of Phenobarbital.

Metabolic dysfunction-associated Steatohepatitis (MASH), is a prominent cause for liver cirrhosis. MASH-cirrhosis is responsible for liver complications and there is no specific treatment. To develop new therapeutic approaches, animal models are needed. The aim of this study was to develop a fast animal model of MASH-cirrhosis in rats reflecting the human disease. Carbon tetrachloride (CCl4) injections in combination with a high-fat Western diet (WD) were used to induce MASH-cirrhosis. To accelerate liver injury, animals received phenobarbital (PB) in their drinking water using two different regimens. Rats developed advanced MASH-cirrhosis characterized by portal hypertension, blood biochemistry, hepatic ballooning, steatosis, inflammation and fibrosis. Importantly, rats receiving low-dose PB for the long term (LT) showed ascites after 6 weeks, whereas rats with high-dose short-term (ST) PB developed ascites after 8 weeks. ST- and LT-treated rats showed increased portal pressure (PP) and decreased mean arterial pressure (MAP). Of note, hepatocyte ballooning was only observed in the LT group. The LT administration of low-dose PB with CCl4 intoxication and WD represents a fast and reproducible rat model mimicking decompensated MASH-cirrhosis in humans. Thus, CCl4 + WD with LT low-dose phenobarbital treatment might be the preferred rat animal model for drug development in MASH-cirrhosis.

African American Females are More Vulnerable to Develop Biliary Injury in NAFLD (Nonalcoholic fatty liver disease) Patients – A Single Institute Experience

Abstract Introduction/Objective Chronic alcohol exposure alone may take decades to induce severe liver disease, yet when combined with elements such as the Western diet, liver pathogenesis accelerates, resulting in earlier symptoms. Identifying the specific contributions of alcohol, diet, and other factors to liver disease is challenging, despite the availability of diagnostic tools like patient histories, liver enzyme tests, imaging, and biopsies. Methods/Case Report This study seeks to detail the liver disease profile of patients who underwent liver biopsies in 2022. Comprehensive profiles were created by retrieving liver biopsy specimens and associated diagnostic data from electronic medical records. Two independent pathologists analyzed the biopsy slides, looking for liver damage associated with alcohol consumption and Western diet influences. We employed enhanced staining techniques to better associate specific types of liver damage with demographic variables. The data analysis was conducted using GraphPad Prism 9 for robust statistical evaluation. Results (if a Case Study enter NA) The research included 88 participants—41 males and 47 females, with average ages of 56 and 62 respectively. The predominant diagnosis was fatty liver disease, with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) accounting for 26% of cases, and alcoholic liver disease (ALD) making up 10%. The NAFLD/NASH group (n=23) consisted mainly of African Americans (n=15) and Caucasians (n=8). Among these, African Americans showed a significantly greater ductular reaction and portal inflammation (p<0.05). Conversely, no notable differences in portal fibrosis and bile stasis were observed between these groups. Notably, African American females (n=11) demonstrated more severe pathological features compared to Caucasian females (n=6), including elevated levels of ductular reaction, fibrosis, portal inflammation, and bile stasis (p<0.05), suggesting a higher vulnerability to biliary injuries. Conclusion The study highlights the complex interplay between lifestyle factors and liver disease development and emphasizes the need for precise diagnostic strategies that consider these multifactorial influences. Additionally, it reveals ethnic disparities in the pathology of NAFLD, advocating for further research into their causes and implications for clinical management. Future investigations should focus on race and gender-specific factors and adapt local healthcare strategies to effectively manage the escalating burden of liver disease.

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.

The influence of perilipin 5 deficiency on gut microbiome profiles in murine metabolic dysfunction-associated fatty liver disease (MAFLD) and MAFLD-hepatocellular carcinoma.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as the leading cause of hepatocellular carcinoma (HCC) worldwide. Over the years, Perilipin 5 (PLIN5) has been recognized as a key regulator of both MAFLD and HCC development. In our previous studies we demonstrated that deficiency in Plin5 reduces the severity of MAFLD and HCC in mice. Interestingly, it has been established that patients with MAFLD and HCC exhibit various changes in their gut microbiome profiles. The gut microbiome itself has been shown to play a role in modulating carcinogenesis and the immune response against cancer. Therefore, we conducted a study to investigate the alterations in fecal microbiome composition in wild type (WT) and Plin5-deficient (Plin5 -/-) mice models of MAFLD and MAFLD-induced HCC (MAFLD-HCC). We utilized 16S rRNA gene sequencing analysis to profile the composition of gut bacteria in fecal samples. Notably, we discovered that the absence of Plin5 alone is already associated with changes in gut microbiota composition. Moreover, feeding the mice a Western diet (WD) resulted in additional microbial alterations. Interestingly, Plin5 -/- animals exhibited an enrichment of the beneficial taxa Lactobacillus in both animal models. Our findings identify Plin5 as a major regulator of gut microbiota during the development of MAFLD and MAFLD-HCC.

Nutritional aspects in neuroendocrine neoplasms. bridging the gap between dietary interventions and cancer care strategies: a scoping review.

Neuroendocrine neoplasms (NENs) represent heterogeneous tumors arising from neuroendocrine cells in different organs. Despite growing interest in the nutritional aspects of NEN management, research in this area is limited. Aim of this review is to summarize the current state of knowledge, highlight research gaps, and underscore the significance of nutrition in the comprehensive care of NEN patients. We conducted an extensive bibliographic search focusing on studies (including retrospective and prospective studies, systematic reviews, case series, and guidelines) exploring the relationship between nutritional assessments, dietary interventions, micronutrient deficiencies, and their impact on NEN outcomes. Significant gaps exist in current research, particularly in understanding the specific nutritional needs of NEN patients and how tailored nutritional interventions can improve clinical outcomes. Evidence suggests that a high-fat Western diet may promote the growth of NEN, while a Mediterranean diet may help lower insulin levels and strengthen the immune system, potentially preventing tumor development. The ketogenic diet and intermittent fasting may also have positive impacts. Addressing common micronutrient deficiencies, such as vitamin D and niacin, is crucial to mitigate disease progression. There's a crucial need for future studies to include a comprehensive nutritional assessment incorporating patient-reported outcomes, to fully capture the impact of nutritional strategies. Nutritional management, an important but under-researched facet of NEN treatment, significantly improves patients' quality of life and survival. Integrating nutrition into personalized cancer care is essential, highlighting the role of nutritional strategies in optimizing patient outcomes.

Effective anti-tumor immune responses are orchestrated by immune cell partnership network that functions through tissue homeostatic pathways, not direct cytotoxicity.

The liver hosts a diverse array of immune cells that play pivotal roles in both maintaining tissue homeostasis and responding to disease. However, the precise contributions of these immune cells in the progression of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) remain unclear. Utilizing a systems immunology approach, we reveal that liver immune responses are governed by a dominant-subdominant hierarchy of ligand-receptor-mediated homeostatic pathways. In healthy individuals, inflammatory immune responses operate within these pathways, challenging the notion of the liver as a purely tolerogenic organ. Chronic consumption of a Western diet (WD) disrupts hepatocyte function and reconfigures immune interactions, resulting in hepatic stellate cells (HSCs), cancer cells, and NKT cells driving 80% of the immune activity during NAFLD. In HCC, 80% of immune response involves NKT cells and monocytes collaborating with hepatocytes and myofibroblasts to restore disrupted homeostasis. Interestingly, dietary correction during NAFLD yields nonlinear outcomes: tumor progression coincides with the failure of mounting homeostatic immune responses, whereas tumor prevention is associated with sustained immune responses, predominantly orchestrated by monocytes. These monocytes actively target fibroblasts and myofibroblasts, creating a tumor-suppressive microenvironment. Notably, only 5% of T cells displayed apoptosis-inducing activity, selectively contributing to the turnover of hepatic stromal cells, particularly myofibroblasts and fibroblasts. Our findings suggest that effective anti-tumor immune responses in the liver are primarily mediated by immune cells sustaining tissue homeostasis, rather than relying on direct cytotoxic mechanisms.

ASGR1 Deficiency Inhibits Atherosclerosis in Western Diet-Fed ApoE-/- Mice by Regulating Lipoprotein Metabolism and Promoting Cholesterol Efflux.

Atherosclerosis is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function ASGR1 (asialoglycoprotein receptor 1) is significantly associated with lower plasma cholesterol levels and reduces cardiovascular disease risk. However, the effect of ASGR1 on atherosclerosis remains incompletely understood; whether inhibition of ASGR1 causes liver injury remains controversial. Here, we comprehensively investigated the effects and the underlying molecular mechanisms of ASGR1 deficiency and overexpression on atherosclerosis and liver injury in mice. We engineered Asgr1 knockout mice (Asgr1-/-), Asgr1 and ApoE double-knockout mice (Asgr1-/-ApoE-/-), and ASGR1-overexpressing mice on an ApoE-/- background and then fed them different diets to assess the role of ASGR1 in atherosclerosis and liver injury. After being fed a Western diet for 12 weeks, Asgr1-/-ApoE-/- mice exhibited significantly decreased atherosclerotic lesion areas in the aorta and aortic root sections, reduced plasma VLDL (very-low-density lipoprotein) cholesterol and LDL (low-density lipoprotein) cholesterol levels, decreased VLDL production, and increased fecal cholesterol contents. Conversely, ASGR1 overexpression in ApoE-/- mice increased atherosclerotic lesions in the aorta and aortic root sections, augmented plasma VLDL cholesterol and LDL cholesterol levels and VLDL production, and decreased fecal cholesterol contents. Mechanistically, ASGR1 deficiency reduced VLDL production by inhibiting the expression of MTTP (microsomal triglyceride transfer protein) and ANGPTL3 (angiopoietin-like protein 3)/ANGPTL8 (angiopoietin-like protein 8) but increasing LPL (lipoprotein lipase) activity, increased LDL uptake by increasing LDLR (LDL receptor) expression, and promoted cholesterol efflux through increasing expression of LXRα (liver X receptor-α), ABCA1 (ATP-binding cassette subfamily A member 1), ABCG5 (ATP-binding cassette subfamily G member 5), and CYP7A1 (cytochrome P450 family 7 subfamily A member 1). These underlying alterations were confirmed in ASGR1-overexpressing ApoE-/- mice. In addition, ASGR1 deficiency exacerbated liver injury in Western diet-induced Asgr1-/-ApoE-/- mice and high-fat diet-induced but not normal laboratory diet-induced and high-fat and high-cholesterol diet-induced Asgr1-/- mice, while its overexpression mitigated liver injury in Western diet-induced ASGR1-overexpressing ApoE-/- mice. Inhibition of ASGR1 inhibits atherosclerosis in Western diet-fed ApoE-/- mice, suggesting that inhibiting ASGR1 may serve as a novel therapeutic strategy to treat atherosclerosis and cardiovascular diseases.

Consequences of acute and long-term excessive iodine intake: A literature review focusing on seaweed as a potential dietary iodine source.

Macroalgae, also called seaweed, are becoming more widespread as food in Western diets. Seaweed can accumulate iodine, an essential nutrient for humans. However, some species of seaweed may contain very high amounts of iodine, and therefore, iodine has been identified as one of the major hazards in the seaweed food chain. Macroalgae may be consumed regularly, though many consumers report eating macroalgae only occasionally. The aim of this paper is to explore possible health consequences of excessive iodine intake according to long-term (chronic) or occasional (acute) excessive exposure to iodine, relating to a regular (chronic) or occasional (acute) seaweed intake, respectively. Furthermore, through a modeling exercise, we add different amounts of seaweed to the diet in a population group to explore the possible safe amounts that can be added without exceeding excessive iodine intakes and risking detrimental health effects. Chronic excessive iodine intakes were associated with several negative health outcomes at variable doses in various studies. For acute excessive iodine exposure, negative health effects seemed to be associated with higher iodine exposures. However, the research on this topic was limited. The chronic and acute iodine exposures needed to result in negative health outcomes may easily be ingested by macroalgae consumption. Adding seaweed to the diet must be done thoughtfully to avoid the risk of exceeding thresholds for excessive iodine intake.

How Do Greeks Feel about Eating Insects? A Study of Consumer Perceptions and Preferences.

Edible insects are considered among the most promising sustainable sources of protein to address the predicted deficiency of conventional food protein. Due to their nutritional and environmental benefits, there is an increasing interest in the ways insects could become part of the Western diet. Little is known about Greek consumers' attitudes toward the habit of consuming insects as food. This study provides insight into Greek consumers' preferences for insect-based food products. The data were collected through an online questionnaire (n = 1531). A two-step cluster analysis and a categorical regression were employed to classify the respondents into discernible clusters and determine the relationship between their socioeconomic characteristics and their willingness to adopt insect-based food products. Feelings of disgust and rejection were the predominant reactions to the concept of insects as food. The acceptance of novel foods derived from edible insects could be potentially enhanced by providing information regarding their positive effects, using familiar food products, and decreasing the insect's degree of visibility by employing processed forms. Finally, the categories of insect protein-enriched food products (bakery, meat, snacks) that Greek consumers are more likely to consume were revealed. Such findings may be useful for promoting strategies regarding consuming insect-based products.

Colorectal Cancer Screening and Management in Low- and Middle-Income Countries and High-Income Countries: A Narrative Review.

Colorectal cancer (CRC) remains a leading global health challenge, being a highly prevalent cancer and a major cause of cancer-related deaths worldwide. The incidence of CRC varies significantly between high-income countries (HICs) and low- and middle-income countries (LMICs), with higher rates of incidence but lower mortality in HICs. Factors such as genetic predisposition, lifestyle, and dietary habits play significant roles in CRC development, with the Western diet and limited access to screening contributing to increased incidence. This review highlights disparities in CRC screening, management, and outcomes between HICs and LMICs, with HICs benefiting from advanced screening methods like colonoscopy and sigmoidoscopy, while LMICs face challenges due to limited healthcare infrastructure and resources. Tailored strategies, including low-cost screening options and community-based initiatives, are critical in LMICs to improve early detection and outcomes. Future directions for improving CRC care globally include telemedicine, artificial intelligence, and mobile health technologies to bridge access gaps, as well as personalized medicine to enhance treatment efficacy. Global collaboration and investment in healthcare infrastructure are necessary to reduce CRC-related mortality, particularly in resource-limited settings.

8421 The Effect of Dietary Glycotoxins on Insulin Resistance in Polycystic Ovary Syndrome

Abstract Disclosure: A. Weidner: None. K. Vann: None. J. Zhang: None. A. Roy: None. O. Astapova: None. Polycystic ovary syndrome (PCOS) is a chronic systemic disorder that affects both metabolism and reproduction. PCOS is characterized by hyperandrogenism and insulin resistance, which are closely intertwined in this disease pathophysiology. PCOS affects an estimated 10% of people with ovaries and increases risk of endometrial cancer, type 2 diabetes, and major cardiovascular events. Furthermore, treatment options are generally poorly tolerated. Despite its prevalence, severity, and enormous public health burden, the etiology of PCOS is not well-understood. Insulin resistance likely plays a central role in PCOS pathogenesis, and often leads to hyperinsulinemia as the pancreas attempts to compensate for insulin’s decreased efficacy in the body. Moreover, the Western diet is becoming increasingly rich in advanced glycation end products (AGEs): non-enzymatically modified biomolecules that have recently been found to have a harmful effect on insulin sensitivity and are associated with diabetes, aging, and oxidative stress. Serum AGE levels have been reported to be higher in both lean and obese PCOS patients, regardless of PCOS subtype. We have also found higher levels of AGE precursors in the serum of our chronic dihydrotestosterone-induced mouse model of PCOS. Using this mouse model, we have shown that ovarian granulosa cells (GCs) remain insulin-sensitive despite systemic insulin resistance and hyperinsulinemia, manifested by impaired glucose tolerance and increased HOMA-IR. To assess whether GCs respond to insulin through alternative receptor pathways, we knocked down insulin receptor in human granulosa-derived KGN cells and found that insulin-stimulated AKT phosphorylation was only minimally reduced, suggesting that insulin may signal in large part through the insulin-like growth factor 1 receptor (IGF1R) in these cells. Therefore, we believe that compensatory hyperinsulinemia plays a key role in chronic GC hyperstimulation, possibly by rerouting the insulin signal through IGF1R to overcome the resistance to insulin receptor activation, suggesting a mechanism for AGE toxicity in PCOS. We hypothesize that in PCOS, this results in impaired GC function and exacerbation of ovarian dysfunction. We will use our PCOS mouse model to study the effects of a reduced-AGE diet in ameliorating the reproductive and metabolic phenotype of an androgenized PCOS mouse. In preliminary experiments, we have found that a low-AGE diet results in lower fasting glucose in C57BL/6J mice after only 4 weeks. We expect that reproductive symptoms, such as estrous cyclicity, and metabolic symptoms, such as GTT and circulating insulin, will improve in our PCOS mouse model when mice are fed a low-AGE diet throughout development and adulthood. This project has significant clinical implications, as reducing dietary AGEs could provide an effective, tolerable, non-drug therapy option for patients with PCOS. Presentation: 6/3/2024

High fat intake aggravates hyperlipidemia and suppresses fatty liver symptoms induced by a high-sucrose diet in rats.

Overconsumption of sucrose or fat is widely acknowledged as a prominent feature of unhealthy dietary patterns. Both factors commonly co-occur and are recognized as hallmarks of the Western diet, which is an important contributor to non-communicative diseases. In this study, we investigated the hazards of high sucrose or fat intake, either alone or in combination. Wistar rats were divided into four groups and fed a control starch diet, high-sucrose diet, high-fat diet, or high-sucrose/fat diet for 30 days. High fat intake increased body weight and visceral and subcutaneous adipose tissue weights. Both high-sucrose and -fat diets were associated with increased plasma triglyceride and glucose levels, and high sucrose also elevated plasma cholesterol levels. The combination of high sucrose and fat synergistically elevated plasma triglyceride levels. The high-sucrose diet increased liver weight and hepatic total lipid and triglyceride levels, whereas this increase was suppressed by the high-fat diet. The high sucrose increased the mRNA levels of hepatic genes involved in fatty acid synthesis and transport (ACLY, ACACA, FAS, ELOVL6, SCD1, SREBP1, and CD36), whereas the high fat suppressed the high sucrose-induced expression of these genes. We observed that high sucrose and fat contents differently exerted their effects on hyperlipidemia and fatty liver. Furthermore, high fat aggravated hyperlipidemia and suppressed fatty liver induced by high sucrose.

A Moderately High-Fat Diet with Proper Nutrient Quality Improves Glucose Homeostasis, Linked to Downregulation of Intestinal CD36 Mediated by the Loss of Desulfovibrio.

The global prevalence of type 2 diabetes mellitus has become a major public health challenge. Dietary intervention is a cornerstone of diabetes management, yet the optimal macronutrient composition remains an open question. In this study, mice were fed a western (W) diet, a moderately high-fat (MHF) diet, a high-protein-high-carbohydrate (HPHC) diet, or a high-protein-low-carbohydrate (HPLC) diet for 22 weeks to compare the effects of different dietary patterns on glucose homeostasis. Our results showed that a MHF diet, under consistent nutrient quality, was most beneficial for glucose metabolism. The MHF diet reduced two key inducers of diabetes─lipid accumulation and inflammation. Downregulation of intestinal CD36 induced by loss of Desulfovibrio colonization restrained lipid absorption and lipopolysaccharide (LPS) transport, which played a crucial role in MHF-mediated resistance to lipid accumulation and inflammation. The findings endorse a dietary pattern featuring MHF of appropriate nutrient quality as an effective strategy for diabetes management.

Hepatic retinol dehydrogenase 11 dampens stress associated with the maintenance of cellular cholesterol levels

ObjectiveDysregulation of hepatic cholesterol metabolism can contribute to elevated circulating cholesterol levels, which is a significant risk factor for cardiovascular disease. Cholesterol homeostasis in mammalian cells is tightly regulated by an integrated network of transcriptional and post-transcriptional signalling pathways. Whilst prior studies have identified many of the central regulators of these pathways, the extended supporting networks remain to be fully elucidated. MethodsHere, we leveraged an integrated discovery platform, combining multi-omics data from 107 strains of mice to investigate these supporting networks. We identified retinol dehydrogenase 11 (RDH11; also known as SCALD) as a novel protein associated with cholesterol metabolism. Prior studies have suggested that RDH11 may be regulated by alterations in cellular cholesterol status, but its specific roles in this pathway are mostly unknown. ResultsHere, we show that mice fed a Western diet (high fat, high cholesterol) exhibited a significant reduction in hepatic Rdh11 mRNA expression. Conversely, mice treated with a statin (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitor) exhibited a 2-fold increase in hepatic Rdh11 mRNA expression. Studies in human and mouse hepatocytes demonstrated that RDH11 expression was regulated by altered cellular cholesterol conditions in a manner consistent with SREBP2 target genes HMGCR and LDLR. Modulation of RDH11 in vitro and in vivo demonstrated modulation of pathways associated with cholesterol metabolism, inflammation and cellular stress. Finally, RDH11 silencing in mouse liver was associated with a reduction in hepatic cardiolipin abundance and a concomitant reduction in the abundance of proteins of the mitochondrial electron transport chain. ConclusionTaken together, these findings suggest that RDH11 likely plays a role in protecting cells against the cellular toxicity that can arise as a by-product of endogenous cellular cholesterol synthesis.

Gene-diet interactions in carbonated sugar-sweetened beverage consumption and metabolic syndrome risk: A machine learning analysis in a large hospital-based cohort

Background and aimCarbonated sugar-sweetened beverages (CSSB) intake has been increasingly linked to metabolic diseases. To investigate the association between CSSB intake and metabolic syndrome (MetS) risk, and the interaction between genetic predisposition to CSSB intake and dietary patterns. MethodsWe examined a hospital-based cohort of 57,940 participants, categorized into low-CSSB (n=52,848) and high-CSSB (n=5,092) groups based on a 50 ml daily consumption cutoff. A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) associated with CSSB intake, and SNP-SNP/SNP-environment interactions were explored. Using XGBoost and deep neural network (DNN) approaches, we developed prediction models for CSSB intake. ResultsThe low- and high-CSSB groups daily consumed an average of 0.56 and 8.91 g sugar from the soda, respectively. The high-CSSB group had unhealthy dietary habits and a lower intake of carotenoids, folate, vitamins C and D, calcium, flavonoids, and phenols than the low-CSSB group, consistent with the results of the prediction models. A polygenic risk score (PRS) based on 6 selected SNPs, linked to genes involved in obesity, diabetes, and nervous system disorders, showed the strongest association with CSSB intake and insulin resistance. Notably, carbohydrate, fat, and Western-style diet (WSD) intake interacted with the PRS, with lower carbohydrate and higher fat and WSD intakes associated with a stronger PRS-sugar intake relationship. The prediction models by XGboost and DNN mainly included dietary factors to explain CSSB intake. ConclusionsA significant interplay between genetic predisposition and poor dietary habits, particularly increased CSSB intake associated with WSD, contributed to MetS risk. It suggested that personalized dietary interventions based on genetic profiles could mitigate MetS risk, especially in populations transitioning to Westernized diets.