Metabolic Factors Research Articles

Gut microbiota and atrial cardiomyopathy

Atrial cardiomyopathy is a multifaceted heart disease characterized by structural and functional abnormalities of the atria and is closely associated with atrial fibrillation and its complications. Its etiology involves a number of factors, including genetic, infectious, immunologic, and metabolic factors. Recent research has highlighted the critical role of the gut microbiota in the pathogenesis of atrial cardiomyopathy, and this is consistent with the gut–heart axis having major implications for cardiac health. The aim of this work is to bridge the knowledge gap regarding the interactions between the gut microbiota and atrial cardiomyopathy, with a particular focus on elucidating the mechanisms by which gut dysbiosis may induce atrial remodeling and dysfunction. This article provides an overview of the role of the gut microbiota in the pathogenesis of atrial cardiomyopathy, including changes in the composition of the gut microbiota and the effects of its metabolites. We also discuss how diet and exercise affect atrial cardiomyopathy by influencing the gut microbiota, as well as possible future therapeutic approaches targeting the gut–heart axis. A healthy gut microbiota can prevent disease, but ecological dysbiosis can lead to a variety of symptoms, including the induction of heart disease. We focus on the pathophysiological aspects of atrial cardiomyopathy, the impact of gut microbiota dysbiosis on atrial structure and function, and therapeutic strategies exploring modulation of the microbiota for the treatment of atrial cardiomyopathy. Finally, we discuss the role of gut microbiota in the treatment of atrial cardiomyopathy, including fecal microbiota transplantation and oral probiotics or prebiotics. Our study highlights the importance of gut microbiota homeostasis for cardiovascular health and suggests that targeted interventions on the gut microbiota may pave the way for innovative preventive and therapeutic strategies targeting atrial cardiomyopathy.

Breast Cancer Risk and Management in the Endocrine Clinic: A Comprehensive Review.

This review seeks to provide endocrine clinicians with a comprehensive analysis of breast cancer risk, diagnostic modalities and management strategies in women with endocrine disorders, with particular emphasis on the influence of metabolic factors such as diabetes and obesity, and the role of Menopausal Hormone Therapy (MHT). The review examines a spectrum of endocrine disorders commonly encountered in clinical practice, including Multiple Endocrine Neoplasia Types 1 (MEN1), 2 (MEN2) and 4 (MEN4), Von Hippel-Lindau syndrome (VHL), Pheochromocytoma and Paraganglioma (PPGL), Acromegaly, Hyperprolactinaemia, Polycystic Ovary Syndrome (PCOS), Congenital Adrenal Hyperplasia (CAH), Turner Syndrome, alongside metabolic conditions such as diabetes and obesity and the effects of MHT. The review critically appraises each disorder's association with breast cancer risk, screening implications and therapeutic management. This analysis focuses on women with the aforementioned endocrine and metabolic disorders, assessing their specific breast cancer risk profiles, informed by the latest clinical evidence and molecular insights. The review comprehensively evaluates current evidence-based approaches to screening, diagnostic accuracy and treatment in this patient cohort. Emphasis is placed on the metabolic derangements, hormonal influences and genetic predispositions that modulate breast cancer risk, providing disorder-specific recommendations for individualised care. The findings indicate a significantly elevated breast cancer risk in patients with MEN1, necessitating early initiation of MRI screening by age 40. In MEN2, emerging evidence suggests that combining RET inhibitors with endocrine therapy may yield clinical benefits, although further research is needed to validate this approach. The breast cancer risk associated with MEN4 and VHL syndromes, while documented, remains less well-characterised, requiring further investigation. Diabetes and obesity are confirmed as major modifiable risk factors, particularly in postmenopausal women, where hyperinsulinemia and metabolic dysfunction contribute to increased incidence and poorer outcomes, notably in triple-negative breast cancer (TNBC). The role of MHT, particularly combined oestrogen-progestogen therapy, is strongly associated with increased breast cancer risk, particularly for hormone receptor-positive malignancies, necessitating cautious use and personalised treatment planning. In contrast, oestrogen-only MHT appears to confer a reduced risk in women post-hysterectomy. For patients with PCOS, CAH and Turner Syndrome, while definitive evidence of elevated breast cancer risk is lacking, individualised screening strategies and careful hormone therapy management remain essential due to the complex interplay of hormonal and metabolic factors. The review highlights the need for personalised breast cancer screening and management protocols in women with endocrine and metabolic disorders. For high-risk groups such as MEN1 patients, early initiation of MRI screening is warranted. In women with diabetes and obesity, targeted interventions addressing hyperinsulinemia and metabolic dysfunction are critical to mitigating their increased cancer risk. The association between MHT and breast cancer underscores the importance of individualised risk stratification in hormone therapy administration, particularly in women with predisposing genetic or endocrine conditions. Enhanced surveillance tailored to the unique risk profiles of endocrine disorder patients will facilitate early detection and improve clinical outcomes. However, further large-scale studies are necessary to refine these associations and develop robust, evidence-based guidelines.

Moderating carbohydrate digestion rate in mice promotes fat oxidation and metabolic flexibility revealed through a new approach to assess metabolic substrate utilization.

Superior metabolic flexibility, or the ability to efficiently switch between oxidation of carbohydrate and fat, is inversely associated with obesity and type 2 diabetes. The influence of dietary factors on metabolic flexibility is incompletely understood. This study examined the impact of dietary carbohydrate digestion rate on metabolic flexibility and metabolic substrate utilization. We employed percent relative cumulative frequency (PRCF) analyses coupled with a new application of modeling using the Mixed Weibull Cumulative Distribution function to examine respiratory exchange ratio (RER) data from adult wild-type mice and mice lacking the mucosal maltase-glucoamylase enzyme (Mgam) under different dietary carbohydrate conditions, with diets matched for total carbohydrate contents and containing different ratios of slowly digestible starch (SDS) and resistant starch (RS), or that were high in sucrose or fat. Fungal amyloglucosidase (AMG) was administered in drinking water to increase carbohydrate digestion rate. We devised a Metabolic Flexibility Factor (MFF) to quantitate metabolic flexibility for each dietary condition and mouse genotype, with higher MFF indicating higher metabolic flexibility. Diets high in SDS exhibited lower average RER and higher metabolic flexibility (MFF) than diets high in resistant starch, sucrose, or fat. Diets containing high and intermediate amounts of SDS led to a more complete shift to fat oxidation. While mouse genotype had minimal effects on substrate oxidation and MFF, AMG supplementation shifted substrate utilization to carbohydrate oxidation and generally decreased MFF. Consumption of slowly digestible carbohydrates improved measures of metabolic substrate utilization at the whole-body level in adult mice.

Long-Term Liver Morbidity and Mortality After Hepatitis C Virus Elimination by Direct-Acting Antivirals.

More accurate stratification of patients with chronic hepatitis C after permanent hepatitis C virus (HCV) clearance by direct-acting antivirals (DAAs) is important for improving long-term surveillance and treatment. The aim of this study was to stratify patients with chronic hepatitis C who are at risk of developing hepatocellular carcinoma (HCC) after HCV cure. This multicenter, retrospective cohort study included 3177 consecutive adult chronic hepatitis C patients without decompensated cirrhosis who were treated with all-oral DAAs. The primary study endpoints were long-term cumulative de novo HCC incidence, HCC recurrence rates, and survival. Additionally, we analyzed the development of HCC by patients without cirrhosis, stratified by age and fibrosis status according to the FIB-4 index. After exclusions, data from 3024 patients were available for analysis. The overall median follow-up period was 6.5 years. None of the patients with non-cirrhosis/FIB-4 < 1.45 (n = 475) developed HCC regardless of background factors. For patients with non-cirrhosis/FIB-4 ≥ 3.25, older age had a greater impact on HCC incidence (log-rank test: p = 0.038). In addition, metabolic factors, including body mass index and diabetes mellitus, were not related to HCC incidence. HCC recurrence commonly occurred within 5 years after HCV cure; nevertheless, HCV cure contributed to an improvement of survival rates. Age is a pivotal factor in predicting de novo HCC development following HCV cure in patients with moderate to advanced fibrosis. Conversely, patients with mild fibrosis (FIB-4 < 1.45) may be eligible for discharge from specialized care after achieving HCV elimination.

Dietary, metabolic and gut microbiota influences on primary ovarian failure: a two-sample Mendelian randomization study.

Previous studies have reported there were associations between ovarian function and dietary factors, metabolic factors and gut microbiota. However, it is unclear whether causal associations exist. We aimed to explore the causal relationship of these factors with risk of primary ovarian failure (POF). Two-sample Mendelian randomization (MR) analysis was performed to genetically predict the causal effects of dietary and metabolic factors and gut microbiota on POF. The inverse variance weighted (IVW) method was used as the primary statistical method. A series of sensitivity analyses, including weighted median, MR-Egger, simple mode, weighted mode methods, and leave-one-out analysis, were conducted to assess the robustness of the MR analysis results. IVW analysis revealed that cigarettes smoked per day, coffee intake and cooked vegetable intake were not causally correlated with POF at the genetic level. However, POF were associated with fresh fruit intake, BMI, Eubacterium (hallii group), Eubacterium (ventriosum group), Adlercreutzia, Intestinibacter, Lachnospiraceae (UCG008), and Terrisporobacter. These findings were robust according to extensive sensitivity analyses. This study identified several dietary factors, metabolic factors and gut microbiota taxa that may be causally implicated in POF, potentially offering new therapeutic targets.

Race/ethnicity-specific association between the American Heart Association's new Life's Essential 8 and stroke in US adults with nonalcoholic fatty liver disease: Evidence from NHANES 2005-2018.

The Life's Essential 8 (LE8) is a recently introduced assessment of cardiovascular health (CVH) by the American Heart Association (AHA). Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease and is associated with an increased risk of stroke. We aimed to explore the association of LE8 with stroke in NAFLD using a national cross-sectional study. Eligible participants with NAFLD aged 20-85years in NHANES 2005-2018 were included. LE8 was assessed according to AHA criteria and categorized into metabolic and behavioral factors. US Fatty Liver Index (USFLI)≥30 and exclusion of other chronic liver diseases suggested NAFLD. Stroke was diagnosed according to self-report on standardized questionnaires. After adjusting for all confounders, each point increase in LE8, LE8 metabolic factors, and LE8 behavioral factors was associated with a 4.4%, 1.8%, and 2.5% reduction in stroke prevalence in NAFLD, respectively. Both moderate and high CVH assessed by LE8 and LE8 behavioral factors were associated with reduced odds of stroke compared with low CVH. Stroke prevalence declined progressively with increasing number of ideal LE8 components, with the lowest odds of stroke at 3+ideal LE8 components for both LE8 metabolic and behavioral factors. Restricted cubic spline suggested dose-response associations. Race/ethnicity was a significant effect modifier, and this association was present only among non-Hispanic white population and other Hispanic population. FLI as a diagnostic indicator of NAFLD yielded generally consistent results. Higher LE8 score, especially LE8 behavioral factors, was associated with reduced prevalence of stroke in NAFLD, especially among non-Hispanic white population and other Hispanic population. The odds of stroke declined progressively with increased ideal LE8 component number. These findings underscore the preventive value of adherence to high CVH for stroke prevention in NAFLD.

Ultra-processed food consumption and risk of dementia and Alzheimer's disease: The Framingham Heart Study.

Ultra-processed food consumption is emerging as a risk factor for various cardiometabolic diseases, however its association with dementia and Alzheimer's disease has rarely been explored. We sought to examine whether ultra-processed food consumption is associated with risk of all-cause dementia and Alzheimer's disease among middle-age and older adults. A prospective cohort study. The Framingham Heart Study, a single-site, community-based cohort study. Offspring cohort participants who attended examination cycles 5 (1991-1995) and 7 (1998-2001) at age ≥60 years and who were dementia-free at baseline. Nutritional information was retrieved from food frequency questionnaires, and ultra-processed food was categorized based on the NOVA system. Participants were followed-up for all-cause dementia and Alzheimer's disease. Cox regression models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) adjusting for potential confounders. The study sample included 1,375 participants free of dementia and stroke at baseline (mean age 68 ± 6y, 54 % females). During a mean follow-up of 12.7 ± 6.0 years, 224 and 172 individuals were diagnosed with all-cause dementia and Alzheimer's disease, respectively. An interaction of ultra-processed food consumption with age was observed with regard to dementia and Alzheimer's disease (p for interaction = 0.02 and 0.007, respectively). Therefore, all analyses were stratified by the median age of 68 years. Among participants who were <68 years of age at baseline, each serving per day of ultra-processed food was associated with 13 % increased risk for Alzheimer's disease (HR = 1.13, 95 % CI:1.03-1.25), and consumption of ≥10 servings/day vs. <10 servings/day of ultra-processed food was associated with a 2.7-fold increase in Alzheimer's disease risk (HR = 2.71, 95 % CI:1.18-6.24), after adjustment for age, sex, education, total energy, metabolic factors and diet quality. The associations with all-cause dementia were less robust, and no significant findings were observed when age at baseline was 68 years or above. Our findings suggest that consumption of ultra-processed food in middle-age may be linked with an increased risk for Alzheimer's disease. Future clinical studies are warranted to assess whether reduction of ultra-processed food consumption improves brain health.

Influence of two sorghum varieties on metabolic factors, microbial community, and flavor component precursors of strong-flavor Baijiu Zaopei

Influence of two sorghum varieties on metabolic factors, microbial community, and flavor component precursors of strong-flavor Baijiu Zaopei

Transcript and Lipid Profile Alterations in Astrocyte-Neuron Mitochondrial Transfer Under Lipopolysaccharide Exposure: An InVitro Study.

Sepsis-associated encephalopathy (SAE) is a brain dysfunction for which no effective therapy currently exists. Recent studies suggest that transferring mitochondria from astrocytes to neurons may benefit SAE patients, though the underlying mechanism remains unclear. We cultured astrocytes and neurons from mice invitro. Astrocytes were stimulated with lipopolysaccharide (LPS) for 24 h, and the astrocyte-conditioned medium (ACM) was collected. Neuronal cultures were then treated with ACM or mitochondria-depleted ACM (mdACM) for further analysis. Mitochondrial transfer was examined under a fluorescence microscope. Western blotting analyzed the protein expression of genes related to apoptosis and mitochondrial metabolism. RNA sequencing and mass spectrometry were employed to investigate the mechanisms underlying mitochondrial transfer. Astrocyte-derived mitochondria migrated toward and connected with LPS-exposed neurons. The addition of ACM significantly attenuated LPS-induced alterations in the proteins linked to apoptosis and mitochondrial dynamics. RNA sequencing revealed notable alterations in the transcript profile of neurons upon ACM treatment, highlighting the involvement of mitochondria metabolism, inflammation, and apoptosis-related factors. Additionally, mitochondrial transfer modified the lipid composition of neurons, increasing phosphatidylserine levels, which correlated with neuroinflammation and enriched pathways related to cytokine and MAPK signaling. Our findings suggest that astrocyte-neuron mitochondrial transfer holds therapeutic potential for alleviating SAE, possibly through the anti-inflammatory effects of lipids, particularly phosphatidylserine.

Short-term negative effects of seawater acidification on the rhodolith holobionts metatranscriptome.

Rhodolith holobionts are formed by calcareous coralline algae (e.g., Corallinales) and associated microbiomes. The largest rhodolith bank in the South Atlantic is located in the Abrolhos Bank, in southwestern Brazil, covering an area of 22,000km2. Rhodoliths serve as nurseries for marine life. However, ocean acidification threatens them with extinction. The acute effects of high pCO₂ levels on rhodolith metatranscriptomes remain unknown. This study investigates the transcriptomic profiles of rhodoliths exposed to short-term (96-h) high pCO₂ levels (up to 1638ppm). Metatranscriptomes were generated for both dead and alive rhodoliths (15.48 million Illumina reads in total). Alive rhodoliths showed an enrichment of gene transcripts related to environmental stress responses and photosynthesis (Cyanobacteria). In contrast, the metatranscriptomes of dead rhodoliths were dominated by heterotrophic (Proteobacteria and Bacteroidetes) metabolism and virulence factors. The rhodolith holobiont metatranscriptomes respond rapidly to short-term acidification (within 1h), suggesting that these holobionts may have some capacity to cope with acute acidification effects. However, the negative impacts of prolonged ocean acidification on rhodolith health cannot be overlooked. Rhodoliths exposed to low pH (7.5) for 96h exhibited a completely altered transcriptomic profile compared to controls. This study highlights the plasticity of rhodolith transcriptomes in the face of ocean acidification and climate change.

Fangchinoline alleviates the progression of osteoarthritis through the nuclear factor kappa B signaling pathway.

Osteoarthritis is a progressive, chronic joint disease characterized by pain, stiffness, and limited mobility, which can lead to physical disability in severe cases. Owing to its complex pathological features, effective treatments for osteoarthritis are lacking. Fangchinoline is a natural alkaloid found in the tuberous roots of plants belonging to the Menispermaceae family. Fangchinoline reportedly possesses anti-inflammatory, antioxidant, and anticancer properties; however, its role in osteoarthritis progression remains unclear. In this study, we investigated the protective effects and potential mechanisms of fangchinoline against osteoarthritis. In vitro, we confirmed that fangchinoline alleviates interleukin-1β-induced cartilage inflammation, reduces the levels of metabolic factors, such as inducible nitric oxide synthase and matrix metalloproteinase-3, and modulates the expression of aggrecan, which enhances extracellular matrix synthesis. In vivo, we demonstrated that fangchinoline can ameliorate articular cartilage degeneration and reduce inflammatory destruction in a destabilization of the medial meniscus mouse model. The nuclear factor kappa B (NF-κB) signaling pathway in osteoarthritis has been a primary target for drug development, and our results suggest that fangchinoline exerts anti-inflammatory effects by inhibiting the activity of IKKα/β. Using an in vitro human cartilage culture model, we further validated that fangchinoline significantly mitigates cartilage degeneration and inflammation by modulating the NF-κB signaling pathway. This evidence highlights its dual action in preserving cartilage integrity and suppressing inflammatory responses. These findings collectively underscore fangchinoline as a potent inhibitor of NF-κB, capable of attenuating key pathological processes associated with osteoarthritis. Therefore, fangchinoline emerges as a promising therapeutic candidate for slowing the progression of osteoarthritis.

RAGE gene polymorphism (rs1800625) and type 1 diabetes mellitus: A potential new model for early diagnosis and risk prediction

Studies have associated advanced glycation end-products (AGEs) and the polymorphism of the AGEs receptor (RAGE) gene with clinical disorders, such as diabetes, in certain ethnic groups. However, its association with type 1 diabetes mellitus (T1DM) in Egyptians has not yet been explored. The aim of this study was to investigate the association between the RAGE gene polymorphism rs1800625 and T1DM susceptibility in Egyptians. A case-control study was conducted with 177 T1DM patients and 177 age- and sex-matched healthy controls. Variables included glycemic markers (fasting blood glucose (FBG), postprandial blood glucose (PBG), hemoglobin A1c (HbA1c)), anthropometric measurements (waist circumference, body mass index (BMI)), lipid profile (total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL)), renal function (albumin-to-creatinine ratio (A/C ratio), serum creatinine), and history of hypertension and smoking. Genotype distribution and allele frequency of the RAGE rs1800625 polymorphism (TT, TC, CC genotypes; T and C alleles) were assessed. This study identified the RAGE rs1800625 polymorphism as a significant genetic factor associated with T1DM susceptibility. The CC genotype was significantly more prevalent in patients compared to controls (29.9% vs 11.9%; OR: 3.62; 95%CI: 1.87–6.97; p&lt;0.001). Similarly, the C allele was more common in patients (54.5% vs 41.0%, OR: 1.73; 95%CI: 1.28–2.33; p&lt;0.001). Multivariate analysis revealed that HbA1c (adjusted OR (aOR): 12.97; 95%CI: 4.00–42.05; p&lt;0.001), FBG (aOR: 8.96; 95%CI: 1.59–50.47; p=0.010), and the rs1800625 polymorphism (aOR: 1.82; 95%CI: 1.146–2.876, p=0.010) were significant predictors of T1DM. In conclusion, a genetic association was found between the RAGE gene polymorphism rs1800625 and T1DM susceptibility, with the CC genotype and C allele being more common in T1DM patients. FBG, HbA1c, and rs1800625 were identified as key predictors for T1DM, with HbA1c being the strongest. These findings highlight the importance of integrating genetic and metabolic factors in managing T1DM.

The “Burden” of Childhood Obesity on Bone Health: A Look at Prevention and Treatment

Childhood obesity represents a multifaceted challenge to bone health, influenced by a combination of endocrine, metabolic, and mechanical factors. Excess body fat correlates with an increase in bone mineral density (BMD) yet paradoxically elevates fracture risk due to compromised bone quality and increased mechanical loading on atypical sites. Additionally, subjects with syndromic obesity, as well as individuals with atypical nutritional patterns, including those with eating disorders, show bone fragility through unique genetic and hormonal dysregulations. Emerging evidence underscores the adverse effects of new pharmacological treatments for severe obesity on bone health. Novel drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists, and bariatric surgery demonstrate potential in achieving weight loss, though limited evidence is available regarding their short- and long-term impacts on skeletal health. This review provides a comprehensive analysis of the mechanisms underlying the impact of childhood obesity on bone health. It critically appraises evidence from in vitro studies, animal models, and clinical research in children with exogenous obesity, syndromic obesity, and eating disorders. It also explores the effects of emerging pharmacological and surgical treatments for severe obesity on skeletal integrity, highlights prevention strategies, and identifies research gaps.

P-1862. Rapid evolution of the Staphylococcus aureus Accessory Gene Regulator system under metabolic stress

Abstract Background The Agr system is the master virulence regulator in Staphylococcus aureus. Active Agr signaling drives acute infections such as abscesses and endocarditis, while dysfunctional signaling is associated with persistent complications and antibiotic tolerance. Agr mutants have been isolated from nares and identified during persistent invasive infections. Thus, Agr loss-of-function mutants are considered an adaptive evolutionary strategy utilized by S. aureus to maintain its presence within hosts. The mechanisms underlying its selection, however, are not well understood. We recently identified genetic and environmental metabolic factors that selects for Agr loss. Agr quorum sensing system in S. aureus The Agr system is the master virulence regulator and is encoded by the agrBDCA operon. The auto-inducing peptide AgrD is matured and transported extracellularly by the membrane protein AgrB. At high enough population density, AgrD accumulates in concentration and is able to activate the surface receptor histidine kinase AgrC, which then signals intracellularly via phosphorylation of the response regulator AgrA. AgrA is a transcription factor that both feed-forwards the agrBDCA operon, as well as driving the expression of numerous virulence factors. Methods Growth, in vitro evolution, and competitive fitness of USA300 JE2 MRSA strains were performed and analyzed in chemically defined media (CDM). The whole genomes of isolates that underwent in vitro evolution were sequenced using an Illumina platform. Agr hemolysis defect was assayed using sheep’s blood agar plates. Growth assays of mutant strains in various CDM. agr mutant strains have enhanced growth under specific amino acid stress. Results We systematically analyzed the growth of a panel of USA300 JE2 MRSA strains (WT, agr, codY, agr/codY) in CDM lacking either single or multiple amino acids. We identified two specific CDM compositions that selectively enhanced the growth kinetics of strains containing agr mutations: (-)TMYISHGF and (-)SG. Growth competition assays in the same two CDM confirmed the fitness advantage of agr mutants. To next assess the physiologic relevance of agr mutations in these media conditions, we performed in vitro evolution and found that both media led to rapid accumulation of Agr loss. We further find that the codY strain, which is deficient in the global metabolic regulator CodY, also selects for agr loss independent of media conditions. Competition assays of mutant strains in various CDM. agr mutant strains have increased growth fitness under specific amino acid stress. Only agrA/codY had increased fitness compared to WT in CDM-TMYISHGF, whereas all mutant strains have increased fitness compared to WT in CDM-SG. Mean values were compared using one-way ANOVA (*, p&amp;lt;0.05; ***, p&amp;lt;0.001; ****, p&amp;lt;0.0001). Conclusion Depending on its status, S. aureus Agr can either drive acute infections or establish a persistent presence. Our identification of genetic and environmental factors that facilitates this lifestyle switch provides valuable insight into how S. aureus adapts within the host during invasive disease. Elucidating the specific mechanisms involved will pave the way to the development of adjunctive anti-metabolism therapeutics that can provide protection against persistent infectious complications. In vitro evolution of agr mutants in various CDM. Tracking hemolysis loss – aka Agr loss – over time reveals both genetic and environmental influences on Agr loss. Genetically encoded codY mutations drive agr mutations via de-repression of QS signaling, whereas specific environmental nutrient stress also drives Agr loss. Disclosures All Authors: No reported disclosures

CC genotype at TCF7L2 diabetes risk locus rs7903146 directs a coordinated fatty acid response to a Mediterranean diet intervention: a randomized controlled trial.

Previous studies identified genetic links between the TCF7L2 C/T variant rs7903146, type 2 diabetes (T2D), and obesity. We wished to deepen our understanding of how specific diets interact with this variant to affect blood metabolites, an aspect not previously investigated. Hence, we conducted a controlled study where individuals with different genotypes followed a Mediterranean (Med) or low-fat (LF) diet for one week. Participants were recruited from the Boston, MA (USA) area. Anthropometric and clinical measures were taken. Genotypes at rs7903146 were ascertained, with homozygous carriers of the more common and protective CC or risk TT genotype invited to participate. Participants followed both diets (LF or Med) for one week with ~10 days' washout between diets. Blood samples taken at the beginning and end of each diet period underwent metabolomics analysis using nuclear magnetic resonance spectroscopy. We evaluated how the diet affected different metabolites based on genetic profile. The cohort of 35 persons was 43% female, aged 18 to 70 y, with BMI between 26.4 to 33.9 kg/m2. Focusing on fatty acids (FAs) and other lipid metabolic factors (n = 23), we observed a greater number and stronger correlations among these factors in the CC genotype-Med diet group than the other three genotype-diet combinations. An aggregate of 11 factors, each negatively correlating with delta saturated fatty acids (SFA), showed a significant genotype-Med diet interaction on delta-SFA in CC individuals on the Med diet (p = 0.0046). A similar genotype-Med diet interaction was observed for delta-monounsaturated fatty acids (MUFA) (p = 0.0078). These interactions were not statistically significant at the end of the LF intervention. Our findings suggest that the Mediterranean diet has stronger influence on regulating lipid factors in individuals with the CC genotype at TCF7L2 variant rs7903146. This diet-genotype interaction may have significant implications for understanding the inter-individual variation of metabolic response on specific dietary regimens.

The Changing pathogenesis of liver cancer in Hawaii over three decades.

Worldwide trends support the increasing contribution of hepatic steatosis on the incidence of hepatocellular carcinoma (HCC). This study investigates if similar changes are seen in Hawaii, where the incidence of HCC is higher than most of the United States. Methods; This is a retrospective study of 1651 patients diagnosed with HCC (1991-2023) that includes 60-70% of Hawaii's HCC cases. We evaluated changes in patient demographics, risk factors, and disease etiology over the three decades. From 1991-2023, there were significant increases in the proportion of HCC cases attributable to metabolic-associated steatotic liver disease(MASLD), coinciding with a rise in the prevalence of metabolic risk factors including obesity, diabetes, hyperlipidemia, and hypertension. Cases with a history of smoking also increased through 2020. Conversely, HCC cases presenting with cirrhosis alone decreased. HCV-associated cases increased through 2015 and then tapered, while HBV-associated cases decreased through 2020. There was no significant change in the proportion of alcohol-associated cases. While HBV continues to be a major contributor to HCC in Hawaii, HCV-related HCC cases have tapered, while metabolic risk factors for HCC and cases attributable to MASLD have increased over time, parallelling overall trends observed in the United States. Efforts are needed to manage these metabolic factors to address the burden of HCC. Impact; Although Hawaii continues to have a large burden of viral hepatitis related HCC, metabolic factors and MASLD have affected the pathogenesis of liver cancer in Hawaii over the past the past 3 decades.

The association between arachidonic acid and gallstone risk: cross-sectional study and Mendelian randomization analysis.

The formation of gallstones is a multifactorial process involving lifestyle habits, lipid metabolism disorders, and genetic factors. This study aims to explore the association between 19 types of dietary fatty acids and gallstone disease using large-scale population data, assess the correlation between dietary fatty acids and serum fatty acids, and investigate the causal relationship between plasma lipids and gallstone disease from a genetic perspective. We employed a cross-sectional study design, combined with logistic regression analysis to evaluate the association between dietary fatty acids and gallstone disease. Pearson correlation analysis was used to assess the correlation between dietary fatty acids and serum fatty acids. Additionally, we utilized Mendelian randomization analysis to explore the causal relationship between plasma lipids and cholelithiasis and performed collocation analysis to identify genetic loci associated with cholelithiasis. Our study demonstrated a significant association between the intake of eicosatetraenoic acid (20:4) and a reduced risk of gallstone disease. The correlation between dietary fatty acids and serum fatty acids was weak, but the intake of eicosatetraenoic acid (20:4) showed a positive correlation with serum levels of arachidonic acid (ARA). Mendelian randomization analysis revealed a protective relationship between plasma lipids containing ARA (20:4) and gallstone disease and identified two SNPs in the FADS1 gene(rs174533 and rs174537)associated with gallstone disease. Our study identifies a significant association between ARA intake and reduced gallstone risk, underscoring its potential in gallstone prevention. The weak correlation between dietary and serum fatty acids suggests complex physiological regulation mechanisms. Mendelian randomization analysis establishes a protective causal link between specific plasma lipids containing ARA and gallstone disease, highlighting the genetic underpinnings of gallstone formation. This research provides a foundation for dietary interventions and underscores the importance of genetic factors in lipid metabolism for future gallstone research and clinical management. Key message What is already known on this topic? Gallstone formation is a multifactorial process, and PUFAs may have a preventive effect, but the specific relationships between dietary fatty acids, serum fatty acids, plasma lipids, and gallstone disease are not well-established. What this study adds? This study finds a significant association between eicosatetraenoic acid (20:4) intake and reduced gallstone risk, and establishes a protective causal link between plasma lipids containing arachidonic acid (20:4) and gallstone disease through Mendelian randomization analysis. How this study might affect research, practice, or policy? The results highlight the potential of dietary interventions targeting eicosatetraenoic acid (20:4) for gallstone prevention and underscore the importance of genetic factors in lipid metabolism for gallstone research and clinical management.

Impact of Obesity on Pubertal Timing and Male Fertility

Abstract: Childhood obesity has profound effects on puberty in boys and girls, altering its timing, progression, and associated hormonal changes. Also, later male fertility could be impaired by childhood and pubertal obesity in light of the impact of inflammatory markers on semen quality. The aim of this narrative review is to explore the intricate relationship between childhood obesity and its impact on pubertal development and fertility, with a specific focus on boys. Such a relationship between obesity and pubertal timing in males is highly influenced by metabolic, hormonal, genetic, epigenetic, and environmental factors. While many studies suggest that obesity accelerates pubertal onset in boys, some studies do not confirm these findings, especially in cases of severe obesity. In fact, delayed puberty has also been reported in certain instances. Obesity influences fertility through different central and peripheral processes, including an altered endocrine milieu, inflammatory environment, and epigenetic modifications that alter semen quality and vitality, leading to subfertility or infertility. The early identification and management of potential issues associated with obesity are crucial for ensuring optimal reproductive health in adulthood. Further research is essential to clarify these associations and to develop targeted interventions aimed at preventing the negative health outcomes associated with obesity-related disruptions in puberty and fertility.

Categorization of Beef Longissimus Lumborum and Gluteus Medius Muscles Based on Metabolic Attributes Is More Informative Than Muscle pH

Muscle metabolism is generally monitored using muscle pH. However, pH does not account for all metabolic effects on meat quality. We evaluated the effectiveness of agglomerative hierarchical clustering in creating clusters of beef longissimus and gluteus medius muscles based on metabolic traits. Beef carcasses (n = 100) were selected at grading based on longissimus thoracis pH (&amp;lt; 5.6, 5.60 to 5.74, 5.75 to 5.9, and &amp;gt; 5.9). Metabolic traits characterizing oxidative and glycolytic metabolism were measured on each muscle. A subset of longissimus lumborum muscles were placed in an in vitro glycolytic system with 2 temperature decline rates to evaluate glycolytic efficiency. Gluteus medius muscles exhibited more oxidative metabolism than longissimus lumborum muscles. Metabolic traits measured in one muscle were generally positively correlated to the same trait measured in the other muscle. Clustering of metabolic traits within each muscle produced similar dendrograms. Clustering of longissimus lumborum muscles based on metabolic traits produced 4 distinct clusters (High pH, Glycolytic, Chaperone, and Soluble). Clustering of the high pH was generally, but not totally, in agreement with classifications based on pH. The remaining longissimus lumborum clusters did not differ in pH. Similar to the longissimus lumborum clusters, the gluteus medius clusters included High pH and Glycolytic clusters and a cluster with low values for protein solubility and peroxiredoxin 2 abundance. In the in vitro system, pH decline was affected by a cluster × temperature decline rate interaction (P &amp;lt; 0.05). The soluble cluster had the least extensive pH decline under the fast temperature decline but had the most rapid pH decline at the slower pH decline. These results indicate that clustering muscles based on several metabolic factors was more effective than categorizing muscles based on muscle pH. Metabolic variation identified by clustering was related to differences in the glycolytic machinery that can be differentially impacted by chilling rate.

Impact of hypertension on liver fibrosis in patients with metabolic dysfunction-associated fatty liver disease.

This study aims to evaluate the association between hypertension and the risk of fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, as well as to investigate the impact of hypertension on the progression of liver fibrosis within this population. We utilized data from the NHANES 2017 to March 2020. Multivariate logistic regression models were employed to control for sociodemographic and metabolic factors to determine the associations between hypertension, MASLD, and fibrosis. Of the total cohort (N = 5,967) 57.92% had hypertension, 38.8% had MASLD, 25.88% had both MASLD and hypertension. Patients with MASLD were more likely to have hypertension (64.24% vs. 44.80%). There was a significant association between stage I (OR1.70, 95% CI: 1.15-2.53) and stage II hypertension (OR1.98, 95% CI: 1.38-2.85) and an increased risk of SF. After adjusting for multiple confounding factors, stage I (OR1.59, 95% CI: 1.09-2.24) and stage II hypertension (OR1.48, 95% CI: 1.06-2.06) remained significantly associated with the risk of SF. Patients with both MASLD and hypertension had higher rates of SF at 14.83% and AF at 7.47%. After adjusting for sociodemographic factors, those patients still had an 8.02-fold increased risk of SF (OR8.02, 95% CI: 4.47-14.39) and a 15.13-fold increased risk of AF (OR15.13, 95% CI: 7.09-32.3). Further adjustment for metabolic factors, those patients still had a significantly higher risk of SF (OR3.07, 95% CI: 1.83-5.14) and AF (OR4.01, 95% CI: 1.48-10.89). MASLD and hypertension are at risk for fibrosis, and the coexistence of the two has a more significant impact on the risk of fibrosis.