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Obesity is a major modifiable risk factor leading to neuroinflammation and neurodegeneration. Excessive fat storage in obesity promotes the progressive infiltration of immune cells into adipose tissue, resulting in the release of pro-inflammatory factors such as cytokines and adipokines. These inflammatory mediators circulate through the bloodstream, propagating inflammation both in the periphery and in the central nervous system. Gut dysbiosis, which results in a leaky intestinal barrier, exacerbates inflammation and plays a significant role in linking obesity to the pathogenesis of neuroinflammation and neurodegeneration through the gut-brain/gut-brain-liver axis. Inflammatory states within the brain can lead to insulin resistance, mitochondrial dysfunction, autolysosomal dysfunction, and increased oxidative stress. These disruptions impair normal neuronal function and subsequently lead to cognitive decline and motor deficits, similar to the pathologies observed in major neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, and Parkinson's disease. Understanding the underlying disease mechanisms is crucial for developing therapeutic strategies to address defects in these inflammatory and metabolic pathways. In this review, we summarize and provide insights into different therapeutic strategies, including methods to alter gut dysbiosis, lifestyle changes, dietary supplementation, as well as pharmacological agents derived from natural sources, that target obesity-induced neuroinflammation and neurodegeneration. [ABSTRACT FROM AUTHOR]

The article "Body and mind: how obesity triggers neuropsychiatric and neurodegenerative disorders" published in Frontiers in Psychiatry explores the intricate relationship between obesity and various neuropsychiatric and neurodegenerative disorders. It highlights how obesity can lead to metabolic dysfunctions that affect the central nervous system, including the hypothalamus, and disrupt neuronal circuits associated with cognition and mood regulation. The article also discusses the role of the gut microbiota in influencing brain function and the shared mechanistic targets between obesity and neuropsychiatric disorders. Additionally, it delves into the bidirectional relationship between obesity and neurodegenerative diseases like Alzheimer's and Parkinson's, emphasizing the impact of metabolic, inflammatory, and hormonal factors on brain health. [Extracted from the article]

Sleep disruption has emerged as a significant public health concern with profound implications for metabolic health. This review synthesizes current evidence demonstrating the intricate relationships between sleep disturbances and cardiometabolic dysfunction. Epidemiological studies have consistently demonstrated that insufficient sleep duration (<7 h) and poor sleep quality are associated with increased risks of obesity, type 2 diabetes, and cardiovascular disease. The underlying mechanisms are multifaceted, involving the disruption of circadian clock genes, alterations in glucose and lipid metabolism, the activation of inflammatory pathways, and the modulation of the gut microbiome. Sleep loss affects key metabolic regulators, including AMPK signaling and disrupts the secretion of metabolic hormones such as leptin and ghrelin. The latest evidence points to the role of sleep-induced changes in the composition and function of gut microbiota, which may contribute to metabolic dysfunction through modifications in the intestinal barrier and inflammatory responses. The NLRP3 inflammasome and NF-κB signaling pathways have been identified as crucial mediators linking sleep disruption to metabolic inflammation. An understanding of these mechanisms has significant implications for public health and clinical practice, suggesting that improving sleep quality could be an effective strategy for preventing and treating cardiometabolic disorders in modern society. [ABSTRACT FROM AUTHOR]

G6PC3 deficiency is a monogenic immunometabolic disorder that causes severe congenital neutropenia type 4. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Here, we investigated the origin and functional consequence of the G6PC3 c.210delC variant found in patients of Mexican descent. Based on the shared haplotypes amongst mutation carriers, we estimated that this variant originated from a founder effect in a common ancestor. Furthermore, by ancestry analysis, we concluded that it appeared in the indigenous Mexican population. At the protein level, we showed that this frameshift mutation leads to an aberrant protein expression in overexpression and patient-derived Epstein-Barr Virus-immortalized B (EBV-B) cells. The neutropenia observed in G6PC3-deficient patients is driven by the intracellular accumulation of the metabolite 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. We characterized how the c.210delC variant impacts glycolysis by performing extracellular flux assays on patient-derived EBV-B cells. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient cells exhibited markedly reduced engagement of glycolysis. Finally, we compared the clinical presentation of patients with the mutation c.210delC and all other G6PC3-deficient patients reported in the literature, and we found that the c.210delC carriers display all prominent clinical features observed in prior patients. In conclusion, G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants. [ABSTRACT FROM AUTHOR]

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as the most common chronic liver disease, is soon to be the leading indication for liver transplantation; however, the diagnosis may remain occult for decades. There is a need for biomarkers that identify patients at risk for MASLD and patients at risk for disease progression to optimize patient management and outcomes. Lymph node adiposity (LNA) is a novel marker of adiposity identified within axillary lymph nodes on screening mammography. Recent studies have demonstrated a correlation between LNA and cardiometabolic disease and cardiovascular disease risk. This study aimed to investigate the association between MASLD and LNA to evaluate the potential of mammographic LNA to serve as an imaging biomarker of MASLD. Methods: We identified women with pathology-proven MASLD who had a liver biopsy and a screening mammogram within 12 months of the liver biopsy. This resulted in a sample size of 161 women for final analysis that met the inclusion criteria. We evaluated lymph node adiposity through multiple measurements of the largest axillary lymph node visualized on mammography and correlated LNA with MASLD histology. Statistical analysis using univariable and multivariable logistic regression and odds ratios was performed using R version 4.1.0 (2021), the R Foundation for Statistical Computing Platform. Results: We found a significant association between MASLD and mammographic LNA, defined as lymph node (LN) length > 16 mm (p = 0.0004) that remained significant after adjusting for clinical factors, including body mass index (BMI). We additionally found a significant association between LNA and metabolic dysfunction-associated steatohepatitis (MASH), identified via liver biopsy (p = 0.0048). Conclusions: Mammographic lymph node adiposity may serve as a helpful imaging biomarker of MASLD in women who have an elevated risk for the development of MASH. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion The co‐occurrence of metabolic dysfunction and neurodegenerative diseases suggests a genetic link, yet the shared genetic architecture and causality remain unclear. We aimed to comprehensively characterise these genetic relationships.We investigated genetic correlations among four neurodegenerative diseases and seven metabolic dysfunctions, followed by bidirectional Mendelian randomisation (MR) to assess potential causal relationships. Pleiotropy analysis (PLACO) was used to detect the pleiotropic effects of genetic variants. Significant pleiotropic loci were refined and annotated using functional mapping and annotation (FUMA) and Bayesian colocalisation analysis. We further explored mapped genes with tissue‐specific expression and gene set enrichment analyses.We identified significant genetic correlations in nine out of 28 trait pairs. MR suggested causal relationships between specific trait pairs. Pleiotropy analysis revealed 25 931 significant single‐nucleotide polymorphisms, with 246 pleiotropic loci identified via FUMA and 55 causal loci through Bayesian colocalisation. These loci are involved in neurotransmitter transport and immune response mechanisms, notably the missense variant rs41286192 in SLC18B1. The tissue‐specific analysis highlighted the pancreas, left ventricle, amygdala, and liver as critical organs in disease progression. Drug target analysis linked 74 unique genes to existing therapeutic agents, while gene set enrichment identified 189 pathways related to lipid metabolism, cell differentiation and immune responses.Our findings reveal a shared genetic basis, pleiotropic loci, and potential causal relationships between metabolic dysfunction and neurodegenerative diseases. These insights highlight the biological connections underlying their phenotypic association and offer implications for future research to reduce the risk of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Objective: Metabolic dysfunction-associated fatty liver disease (MAFLD) has been used to characterize patients with fatty liver and metabolic dysfunction. The association between MAFLD and chronic kidney disease (CKD) remains undefined. We present high-quality evidence obtained from cohort studies examining if MAFLD leads to an increased risk of CKD. Methods: PubMed, CENTRAL, Embase, Scopus, and Web of Science were searched from the earliest possible date to 17th May 2024 for cohort studies examining the link between MAFLD and CKD. Results: Eight studies with nine cohorts were included. Pooled analysis of all nine cohorts showed that MAFLD was an independent predictor of CKD (HR: 1.38 95% CI: 1.24, 1.53 I2 = 95%). No change in results was noted on sensitivity analysis. We also noted no change in the significance of effect size on subgroup analysis based on study design (prospective or retrospective), country of origin (China, Korea, Japan, or UK), the incidence of CKD in the cohort (> 10% or ≤ 10%) and if the study adjusted for cardiovascular disease, diabetes, hypertension, and smoking status. Further, meta-analysis showed that MAFLD was still a risk factor for CKD in men (HR: 1.38 95% CI: 1.22, 1.56 I2 = 86%), women (HR: 1.51 95% CI: 1.25, 1.82 I2 = 87%), overweight (HR: 1.41 95% CI: 1.20, 1.66 I2 = 89%) and non-overweight cohorts (HR: 1.35 95% CI: 1.20, 1.53 I2 = 9%). Conclusion: MAFLD is an independent predictor of CKD. The association seems persistent irrespective of sex, body mass index, and other CKD risk factors. [ABSTRACT FROM AUTHOR]

Dysregulation of energy metabolism, including hyperglycemia, insulin resistance and fatty liver have been reported in a substantial proportion of lean children. However, non-obese murine models recapitulating these features are lacking to study the mechanisms underlying the development of metabolic dysregulations in lean children. Here, we develop a model of diet-induced metabolic dysfunction without obesity in juvenile mice by feeding male and female mice a diet reflecting Western nutritional intake combined with protein restriction (mWD) during 5 weeks after weaning. mWD-fed mice (35% fat, 8% protein) do not exhibit significant weight gain and have moderate increase in adiposity compared to control mice (16% fat, 20% protein). After 3 weeks of mWD, juvenile mice have impaired glucose metabolism including hyperglycemia, insulin resistance and glucose intolerance. mWD also triggers hepatic metabolism alterations, as shown by the development of simple liver steatosis. Both male and female mice fed with mWD displayed metabolic dysregulation, which a probiotic treatment with Lactiplantibacillus plantarum WJL failed to improve. Overall, mWD-fed mice appear to be a good preclinical model to study the development of diet-induced metabolic dysfunction without obesity in juveniles. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction and obesity are closely related to chronic kidney disease (CKD). However, studies on the relationship between various metabolic syndrome-body mass index (MetS-BMI) phenotypes and the risk of CKD in the Chinese population have not yet been explored. Materials and methods: Data from the China Health and Retirement Longitudinal Study (CHARLS) 2015 were analyzed in this study. This study enrolled 12,054 participants. Participants were divided into six distinct groups according to their MetS-BMI status. Across the different MetS-BMI groups, the odd ratios (ORs) for CKD were determined using multivariable logistic regression models. Results: The prevalence of CKD was higher in metabolically unhealthy groups than in the corresponding healthy groups. Moreover, the fully adjusted model showed that all metabolically unhealthy individuals had an increased risk of developing CKD compared to the metabolically healthy normal weight group (OR = 1.62, p = 0.002 for the metabolically unhealthy normal weight group; OR = 1.55, p < 0.001 for the metabolically unhealthy overweight group; and OR = 1.77, p < 0.001 for the metabolically unhealthy obesity group. Conclusions: This study is the first to evaluate the relationship between the MetS-BMI phenotype and renal prognosis in the Chinese population. Individuals with normal weights are at different risk of developing CKD depending on their different metabolic phenotypes. [ABSTRACT FROM AUTHOR]

Despite many years of research into the complex neurobiology of Parkinson's disease, the precise aetiology cannot be pinpointed down to one causative agent but rather a multitude of mechanisms. Current treatment options can alleviate symptomsbut only slightly slow down the progression and not cure the disease and its underlying causes. Factors that play a role in causing the debilitating neurodegenerative psycho-motoric symptoms include genetic alterations, oxidative stress, neuroinflammation, general inflammation, neurotoxins, iron toxicity, environmental influences, and mitochondrial dysfunction. Recent findings suggest that the characteristic abnormal protein aggregation of alpha-synuclein and destruction of substantia nigra neurons might be due to mitochondrial dysfunction related to disturbances in lipid and glucose metabolism along with insulin resistance. The latter mechanism of action might be mediated by insulin receptor substrate docking to proteins that are involved in neuronal survival and signaling related to cell destruction. The increased risk of developing Type 2 Diabetes Mellitus endorses a connection between metabolic dysfunction and neurodegeneration. Here, we explore and highlight the potential role of glycolipid cellular insults in the pathophysiology of the disorder, opening up new promising avenues for the treatment of PD. Thus, antidiabetic drugs may be employed as neuromodulators to hinder the progression of the disorder. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to evaluate the effectiveness and safety of a nutraceutical combination given to insulin-resistant overweight patients with altered lipid profiles. To this end, an observational study was designed in which 74 individuals (50 females and 24 males) underwent an observational period of 3 months. Methods: During this time, a specific nutraceutical combination containing myo-inositol, glycine, Coprinus comatus, α-lipoic acid, phlorizin, zinc, vitamin B6, and chromium picolinate was administered. Patients were asked not to modify their lifestyles so that no variable that might interfere with results was introduced. Results: After the 3-month period, the obtained data revealed that insulin levels significantly decreased with respect to the baseline, while glucose levels exhibited a trend towards lower concentrations, which was not significant. In addition, HOMA-IR index, body weight, BMI, and abdominal circumference values all decreased significantly. Regarding lipid profiles, the data obtained before and after the 3-month period showed statistically significant decreases in concentrations of total cholesterol, LDL cholesterol, and triglyceride, as well as a small but statistically significant concomitant increase in HDL cholesterol. Conclusions: Thus, on the basis of these data, it may be stated that the specific nutraceutical combination used in the present study significantly ameliorated a number of metabolic parameters without measurable side effects. The efficacy and safety of the product were, therefore, confirmed in our group of patients. [ABSTRACT FROM AUTHOR]

Purpose: Diabetes mellitus (DM) and epilepsy and the psychological and socio-economic implications that are associated with their treatments can be quite perplexing. Metformin is an antihyperglycemic medication that is used to treat type 2 DM. In addition, metformin elicits protective actions against multiple diseases, including neurodegeneration and epilepsy. Recent studies indicate that metformin alters the resident gut microbiota in favor of species producing agmatine, an arginine metabolite which, in addition to beneficially altering metabolic pathways, is a potent neuroprotectant and neuromodulant. Methods: We first examine the literature for epidemiological and clinical evidences linking DM and epilepsy. Next, basing our analyses on published literature, we propose the possible complementarity of agmatine and metformin in the treatment of DM and epilepsy. Results: Our analyses of the clinical data suggest a significant association between pathogeneses of epilepsy and DM. Further, both agmatine and metformin appear to be multimodal therapeutic agents and have robust antiepileptogenic and antidiabetic properties. Data from animal and clinical studies largely support the use of metformin/agmatine as a double-edged pharmacotherapeutic agent against DM and epilepsy, particularly in their concurrent pathological occurrences. Conclusion: The present review explores the evidences and available data on possible uses of metformin/agmatine as pertinent antidiabetic and antiepileptic agents. Our hope is that this will stimulate further research on the therapeutic actions of these multimodal agents, particularly for subject-specific clinical outcomes. [ABSTRACT FROM AUTHOR]

Background/Objectives: Low fasting blood lysosomal acid lipase (LAL) activity is associated with the pathogenesis of metabolic hepatic steatosis. We measured LAL activity in blood and plasma before and after an oral fat tolerance test (OFTT) in patients with metabolic-dysfunction-associated steatotic liver disease (MASLD). Methods: Twenty-six controls and seventeen patients with MASLD but without diabetes were genotyped for the patatin-like phospholipase 3 (PNPLA3) rs738409 variant by RT-PCR and subjected to an OFTT, measuring LAL activity in blood and plasma with a fluorimetric method. Results: LAL activity in blood both under fasting and 4 h after OFTT (0.846 ± 0.309 nmol/spot/h vs. 1.180 ± 0.503 nmol/spot/h p < 0.01) was lower in patients with MASLD compared to controls. These differences were present only in carriers of the PNPLA3 variant. In controls not carrying the PNPLA3 variant, the postprandial increase in blood LAL activity was negatively correlated with that of serum triglycerides (p < 0.05). Extracellular LAL activity in plasma was lower in patients with MASLD (n = 9) compared to controls (n = 8) in the fasting state (p < 0.01) and 4 h post-meal (p < 0.05). The area under the curve up to 6 h of plasma LAL activity was lower in patients with MASLD than in controls (p < 0.05) and correlated negatively with that of triglycerides only in controls (r = −0.841; p < 0.01). Conclusions: Patients with MASLD have reduced LAL activity in blood and plasma both before and 4 h after a meal. In patients with MASLD, the physiological negative correlation between circulating LAL levels and postprandial hypertriglyceridemia is lost. [ABSTRACT FROM AUTHOR]

Abstract Objective Metabolic dysfunction-associated fatty liver disease (MAFLD) has been used to characterize patients with fatty liver and metabolic dysfunction. The association between MAFLD and chronic kidney disease (CKD) remains undefined. We present high-quality evidence obtained from cohort studies examining if MAFLD leads to an increased risk of CKD. Methods PubMed, CENTRAL, Embase, Scopus, and Web of Science were searched from the earliest possible date to 17th May 2024 for cohort studies examining the link between MAFLD and CKD. Results Eight studies with nine cohorts were included. Pooled analysis of all nine cohorts showed that MAFLD was an independent predictor of CKD (HR: 1.38 95% CI: 1.24, 1.53 I2 = 95%). No change in results was noted on sensitivity analysis. We also noted no change in the significance of effect size on subgroup analysis based on study design (prospective or retrospective), country of origin (China, Korea, Japan, or UK), the incidence of CKD in the cohort (> 10% or ≤ 10%) and if the study adjusted for cardiovascular disease, diabetes, hypertension, and smoking status. Further, meta-analysis showed that MAFLD was still a risk factor for CKD in men (HR: 1.38 95% CI: 1.22, 1.56 I2 = 86%), women (HR: 1.51 95% CI: 1.25, 1.82 I2 = 87%), overweight (HR: 1.41 95% CI: 1.20, 1.66 I2 = 89%) and non-overweight cohorts (HR: 1.35 95% CI: 1.20, 1.53 I2 = 9%). Conclusion MAFLD is an independent predictor of CKD. The association seems persistent irrespective of sex, body mass index, and other CKD risk factors.

The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Obesity-related conditions like type 2 diabetes and non-alcoholic fatty liver disease exacerbate this relationship. Peripheral lipid accumulation, particularly in the liver, initiates a cascade of inflammatory processes that extend to the brain, influencing critical metabolic regulatory regions. Ceramide and palmitate, key lipid components, along with lipid transporters lipocalin-2 and apolipoprotein E, contribute to neuroinflammation by disrupting blood–brain barrier integrity and promoting gliosis. Peripheral insulin resistance further exacerbates brain insulin resistance and neuroinflammation. Preclinical interventions targeting peripheral lipid metabolism and insulin signaling pathways have shown promise in reducing neuroinflammation in animal models. However, translating these findings to clinical practice requires further investigation into human subjects. In conclusion, metabolic dysfunction, peripheral inflammation, and insulin resistance are integral to neuroinflammation and neurodegeneration. Understanding these complex mechanisms holds potential for identifying novel therapeutic targets and improving outcomes for neurodegenerative diseases.

Abstract This study aimed to address the diagnostic challenges in distinguishing between alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). We utilized whole-slide imaging technology to conduct a comprehensive digital analysis of liver specimens collected from patients undergoing transplantation. This study included 36 and 17 patients with ALD and MASLD cirrhosis, respectively, who underwent transplantation at our institution. Digital slides were analyzed for fibrosis patterns using FibroNest™. Patient background characteristics were comparable between ALD (n = 36) and MASLD (n = 17) groups, except for sex. The ALD group exhibited thicker collagen per strand, longer and more flexural fibrosis, and a more heterogeneous distribution than the MASLD group. In patients with ALD and concomitant metabolic dysfunction, fiber distribution became relatively uniform, resembling MASLD. Application of the phenotypic fibrosis composite score achieved 100% sensitivity and specificity for ALD/MASLD diagnosis. Digital pathological analysis of the fibrosis patterns showed morphological differences between ALD and MASLD. This approach holds promise for histological differentiation, providing valuable insights beyond the current definitions based solely on alcohol intake. This study emphasizes the potential of digital pathology in refining the diagnostic criteria for hepatic disorders.

Background and Purpose: Antipsychotics such as olanzapine are associated with significant metabolic dysfunction, attributed to gut microbiome dysbiosis. A recent notion that most psychotropics are detrimental to the gut microbiome has arisen from consistent findings of metabolic adverse effects. However, unlike olanzapine, the metabolic effects of lurasidone are conflicting. Thus, this study investigates the contrasting effects of olanzapine and lurasidone on the gut microbiome to explore the hypothesis of 'gut neutrality' for lurasidone exposure. Experimental Approach: Using Sprague–Dawley rats, the effects of olanzapine and lurasidone on the gut microbiome were explored. Faecal and blood samples were collected weekly over a 21‐day period to analyse changes to the gut microbiome and related metabolic markers. Key Results: Lurasidone triggered no significant weight gain or metabolic alterations, instead positively modulating the gut microbiome through increases in mean operational taxonomical units (OTUs) and alpha diversity. This novel finding suggests an underlying mechanism for lurasidone's metabolic inertia. In contrast, olanzapine triggered a statistically significant decrease in mean OTUs, substantial compositional variation and a depletion in short‐chain fatty acid abundance. Microbiome depletion correlated with metabolic dysfunction, producing a 30% increase in weight gain, increased pro‐inflammatory cytokine expression, and increased blood glycaemic and triglyceride levels. Conclusion and Implications: Our results challenge the notion that all antipsychotics disrupt the gut microbiome similarly and highlights the potential benefits of gut‐neutral antipsychotics, such as lurasidone, in managing metabolic side effects. Further research is warranted to validate these findings in humans to guide personalised pharmacological treatment regimens for schizophrenia. [ABSTRACT FROM AUTHOR]

Microplastics (MPs) have attracted significant attention due to their global distribution in living environments. Although some studies have reported MP-induced hepatotoxicity in mouse models, a systematic approach to MP-mediated liver toxicity was still lacking. Therefore, we used a mouse model to study the sub-chronic effects of MP exposure on the liver. Female C57BL/6 mice, aged 6 weeks, received an oral administration of 0.3 mg of Nile Red-labeled polystyrene (PS) microplastics, with particle sizes of 0.5 µm (submicron) and 5 µm (micron), via gavage, while control mice received vehicle only. Each mouse was exposed to MPs twice a week for 12 weeks. After sacrifice, the levels of MP accumulation, oxidative stress, inflammation, and pathological changes were measured in the mouse liver, and blood samples were collected for serum biochemistry analysis. Our results demonstrated that 0.5 µm PS-MPs were accumulated in mouse livers post-MP exposure, but not in the 5 µm MP exposure group. Simultaneously, increased levels of glucose, triglyceride, alanine transaminase (ALT), aspartate transaminase (AST), superoxide dismutase, 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), interleukin-6, and lipid droplets were found in the 0.5 µm MP exposure group, while the fewer responses, including elevated liver weight index, glucose, high-density lipoprotein, AST, and decreased HNE-MA were observed in 5 µm MP exposure group. These results indicate that sub-chronic exposure to submicron MPs causes MP deposition in mouse livers, which further induces oxidative stress, increases inflammatory cytokines and perturbs glucose and lipid homeostasis, which might trigger more severe metabolic dysfunction or non-alcoholic steatohepatitis-like hepatotoxicity. [ABSTRACT FROM AUTHOR]

Introduction: 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. Methods: 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. Results: 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. Discussion: Our findings identify Plin5 as a major regulator of gut microbiota during the development of MAFLD and MAFLD-HCC. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated fatty liver disease (MAFLD) is spreading worldwide, largely due to unhealthy lifestyles that contribute to the rise in diabetes, metabolic syndrome, and obesity. In this situation, the progression of injury to metabolic steatohepatitis can evolve to cirrhosis and, eventually, to hepatocellular carcinoma (HCC). It is well known that serine protease enzymes with different functions in cellular homeostasis act as signaling molecules that regulate liver inflammation by activating the protease-activated receptors (PARs) family members, expressed on the cellular plasma membrane. Among them, PAR2 plays a central role in the activation of signaling pathways in response to changes in the extracellular microenvironment. Experimental data have provided evidence that PAR2 is involved not only in inflammatory response but also in insulin resistance, lipid metabolism, and cancer. The major aims of this narrative review are addressed to assess PAR2 involvement in inflammation, metabolism, and liver disease progression and to explore possible therapeutic strategies, based on PAR2 inhibition, in order to prevent its biological effects in the context of MAFLD and cancer. [ABSTRACT FROM AUTHOR]

This study aimed to address the diagnostic challenges in distinguishing between alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). We utilized whole-slide imaging technology to conduct a comprehensive digital analysis of liver specimens collected from patients undergoing transplantation. This study included 36 and 17 patients with ALD and MASLD cirrhosis, respectively, who underwent transplantation at our institution. Digital slides were analyzed for fibrosis patterns using FibroNest™. Patient background characteristics were comparable between ALD (n = 36) and MASLD (n = 17) groups, except for sex. The ALD group exhibited thicker collagen per strand, longer and more flexural fibrosis, and a more heterogeneous distribution than the MASLD group. In patients with ALD and concomitant metabolic dysfunction, fiber distribution became relatively uniform, resembling MASLD. Application of the phenotypic fibrosis composite score achieved 100% sensitivity and specificity for ALD/MASLD diagnosis. Digital pathological analysis of the fibrosis patterns showed morphological differences between ALD and MASLD. This approach holds promise for histological differentiation, providing valuable insights beyond the current definitions based solely on alcohol intake. This study emphasizes the potential of digital pathology in refining the diagnostic criteria for hepatic disorders. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction associated fatty liver disease (MAFLD) is an increasing public health problem, affecting one third of the global population. Contrary to conventional wisdom, MAFLD is not exclusive to obese or overweight individuals. Epidemiological studies have revealed a remarkable prevalence among healthy weight individuals, leading investigations into the genetic, lifestyle, and dietary factors that contribute to the development of MAFLD in this population. This shift in perspective requires reconsideration of preventive strategies, diagnostic criteria and therapeutic approaches tailored to address the unique characteristics of MAFLD healthy weight individuals. It also underscores the importance of widespread awareness and education, within the medical community and among the general population, to promote a more inclusive understanding of liver metabolic disorders. With this review, we aim to provide a comprehensive exploration of MAFLD in healthy weight individuals, encompassing epidemiological, pathophysiological, and clinical aspects. [ABSTRACT FROM AUTHOR]

The most common chronic liver illness worldwide is metabolic dysfunction linked to fatty liver disease (MAFLD), which is poorly understood by doctors and patients. Many people with this disease develop steatohepatitis, cirrhosis and its consequences, as well as extrahepatic manifestations; these conditions are particularly common if they are linked to diabetes mellitus or obesity. A breakthrough with numerous benefits is the switch from NAFLD to MAFLD in terms of terminology and methodology. The diagnosis of MAFLD is based on affirmative criteria; unlike NAFLD, it is no longer based on exclusion. The diagnosis of MAFLD and the evaluation of steatosis and fibrosis is achieved using liver biopsy and non-invasive laboratory or radiographic techniques. We briefly address the most recent developments in MAFLD epidemiology and diagnosis. [ABSTRACT FROM AUTHOR]

The introduction of the term "Metabolic Steatotic Liver Disease" (MASLD) underscores the critical role of metabolic dysfunction in the development and progression of chronic liver disease and emphasizes the need for strategies that address both liver disease and its metabolic comorbidities. In recent years, a liver-focused perspective has revealed that altered endocrine function of the fatty liver is a key contributor to the metabolic dysregulation observed in MASLD. Due to its secretory capacity, the liver's increased production of proteins known as "hepatokines" has been linked to the development of insulin resistance, explaining why MASLD often precedes dysfunction in other organs and ultimately contributes to systemic metabolic disease. Among these hepatokines, fibroblast growth factor 21 (FGF21) and fetuin-A play central roles in regulating the metabolic abnormalities associated with MASLD, explaining why their dysregulated secretion in response to metabolic stress has been implicated in the metabolic abnormalities of MASLD. This review postulates why their modulation by GLP1-Ras may mediate the beneficial metabolic effects of these drugs, which have increased attention to their emerging role as pharmacotherapy for MASLD. By discussing the crosstalk between GLP1-Ras-FGF21-fetuin-A, this review hypothesizes that the possible modulation of fetuin-A by the novel GLP1-FGF21 dual agonist pharmacotherapy may contribute to the management of metabolic and liver diseases. Although research is needed to go into the details of this crosstalk, this topic may help researchers explore the mechanisms by which this type of pharmacotherapy may manage the metabolic dysfunction of MASLD. [ABSTRACT FROM AUTHOR]

Aims: Metabolic associated fatty liver disease (MAFLD) was proposed to replace "non‐alcoholic fatty liver disease (NAFLD) with new diagnostic criteria." The group meeting these two diagnostic criteria is called "Overlapping Fatty Liver Disease (FLD)." Its clinical characteristics remain unknown. Methods: This study included participants from the Taiwan Bio‐Bank database, where NAFLD was defined as hepatic steatosis in liver ultrasound, with exclusion of other known chronic liver diseases. MAFLD was defined as the presence of hepatic steatosis plus metabolic dysfunction, defined as having any of following three criteria: overweight/obesity, type 2 diabetes mellitus (DM), or ≥2 metabolic risk abnormalities in lean/normal weight subjects. According to these two diagnostic criteria, three groups were identified: "overlapping FLD", "NAFLD alone", and "MAFLD alone." NAFLD fibrosis score (NFS) >0.675 was defined as advanced liver fibrosis. Results: Eight thousand thirty‐eight NAFLD participants (age 55.86 ± 10.12; males 41.07%) were included in the final analysis. Of them, "overlapping FLD" was diagnosed in 7377 (91.8%) and "NAFLD alone" in 661 (8.2%) participants. "Overlapping FLD" patients were older and had a higher percentage of male, worse metabolic profiles, higher NFS, and the percentage of carotid plaques was higher than those with "NAFLD alone." Multivariate analysis showed age, hypertension, DM, and BMI were positively associated with advanced liver fibrosis in "overlapping FLD" patients. Conclusions: "Overlapping FLD" is better for liver research due to identifying a high‐risk population among NAFLD patients. NAFLD definition introduces the heterogeneity through "NAFLD alone" group and MAFLD criteria overcome this limitation. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a prevalent joint disorder and the most common form of arthritis, affecting approximately 500 million people worldwide, or about 7% of the global population. Its pathogenesis involves a complex interplay between metabolic dysfunction and gut microbiome (GM) alterations. This review explores the relationship between metabolic disorders—such as obesity, diabetes, and dyslipidemia—and OA, highlighting their shared risk factors, including aging, sedentary lifestyle, and dietary habits. We further explore the role of GM dysbiosis in OA, elucidating how systemic inflammation, oxidative stress, and immune dysregulation driven by metabolic dysfunction and altered microbial metabolites contribute to OA progression. Additionally, the concept of "leaky gut syndrome" is discussed, illustrating how compromised gut barrier function exacerbates systemic and local joint inflammation. Therapeutic strategies targeting metabolic dysfunction and GM composition, including lifestyle interventions, pharmacological and non-pharmacological factors, and microbiota-targeted therapies, are reviewed for their potential to mitigate OA progression. Future research directions emphasize the importance of identifying novel biomarkers for OA risk and treatment response, adopting personalized treatment approaches, and integrating multiomics data to enhance our understanding of the metabolic–GM–OA connection and advance precision medicine in OA management. [ABSTRACT FROM AUTHOR]

Both heart failure with preserved ejection fraction (HFpEF) and non-alcoholic fatty liver disease (NAFLD) develop due to metabolic dysregulation, has similar risk factors (e.g., insulin resistance, systemic inflammation) and are unresolved clinical challenges. Therefore, the potential link between the two disease is important to study. We aimed to evaluate whether NASH is an independent factor of cardiac dysfunction and to investigate the age dependent effects of NASH on cardiac function. C57Bl/6 J middle aged (10 months old) and aged mice (24 months old) were fed either control or choline deficient (CDAA) diet for 8 weeks. Before termination, echocardiography was performed. Upon termination, organ samples were isolated for histological and molecular analysis. CDAA diet led to the development of NASH in both age groups, without inducing weight gain, allowing to study the direct effect of NASH on cardiac function. Mice with NASH developed hepatomegaly, fibrosis, and inflammation. Aged animals had increased heart weight. Conventional echocardiography revealed normal systolic function in all cohorts, while increased left ventricular volumes in aged mice. Two-dimensional speckle tracking echocardiography showed subtle systolic and diastolic deterioration in aged mice with NASH. Histologic analyses of cardiac samples showed increased cross-sectional area, pronounced fibrosis and Col1a1 gene expression, and elevated intracardiac CD68+ macrophage count with increased Il1b expression. Conventional echocardiography failed to reveal subtle change in myocardial function; however, 2D speckle tracking echocardiography was able to identify diastolic deterioration. NASH had greater impact on aged animals resulting in cardiac hypertrophy, fibrosis, and inflammation. [ABSTRACT FROM AUTHOR]

Purpose: Hypothyroidism is an endocrine disorder characterised by decreased T3, T4 and increased TSH levels. This study aims to examine the potential effects of Ferulic acid (FA) on rats with hypothyroidism induced by propylthiouracil through the estimation of biochemical parameters and histopathological studies. Methods: Twenty-five female wistar rats were allocated into five groups: Control group [1% CMC, p.o.], Disease group [PTU-50 mg/kg, p.o.], [Levothyroxine (LT4) group - 20 µg/kg, p.o. + PTU-50 mg/kg, p.o.], [FA -25 mg/kg, p.o. + PTU-50 mg/kg, p.o.] and [FA 50 mg/kg, p.o. + PTU-50 mg/kg, p.o.]. On 15th day blood was collected and serum was separated for estimation of biochemical parameters, liver and kidney homogenate was utilised for the estimation of oxidative stress markers and the thyroid gland was dissected to examine histological features. Results: PTU administration for 14 days showed a substantial decline in T3 and T4 and increases in TSH levels. PTU-administered rats significantly increased TC, TG and LDL levels, and decreased HDL levels. AST, ALT, urea, creatinine, and IL-6 were determined and these levels were significantly altered in PTU-induced hypothyroid group. In hypothyroid rats MDA, NO, GSH and SOD levels were significantly altered. However, treatment with FA for 14 days attenuated PTU-induced alterations. Furthermore, FA improves the histological changes of the thyroid gland. Conclusion: In conclusion, FA treatment showed a protective effect against hypothyroidism by stimulating the thyroid hormones through the activation of thyroid peroxidase enzyme and improving thyroid function. In addition, FA diminished the increase in lipids, liver and kidney markers, oxidative stress and inflammation. Highlights: Hypothyroidism induced by PTU is ameliorated by ferulic acid in rats Ferulic acid showed a protective effect on thyroid hormones and lipid profile Ferulic acid inhibits oxidative stress and inflammation Ferulic acid improved the structure and integrity of the thyroid gland [ABSTRACT FROM AUTHOR]

Aging‐related metabolic disorders seriously affect the lifespan of middle‐aged and older people, potentially due to disruptions in the adaptive immune and gut microbial profiles. Dietary intervention offers a promising strategy for maintaining metabolic health. This study aimed to investigate the ameliorative effect of 2′‐fucosyllactose (2'‐FL) on aging‐induced metabolic dysfunction and the underlying mechanisms. The results revealed that 2'‐FL significantly relieved aging‐related metabolic disorders, including weight gain, lipid deposition, dyslipidemia, glucose intolerance, systemic inflammation, and abnormal hepatic metabolism. Flow cytometry analysis revealed a significant reduction in T cytotoxic (Tc), T helper (Th), and regulatory T (Treg) cells and a significant increase in Th17 cells in aged mice, while 2'‐FL relieved the aging‐induced proportional changes in Th and Th17 subtypes. The aging intestinal microecology was characterized by higher Th17/Treg ratios, impaired gut barrier function, lower gut bacterial diversity, decreased abundance of beneficial genera including Ligilactobacillus, Colidextribacter, Mucispirillum, and Lachnoclostridium, and increased abundance of harmful bacteria including Turicibacter and Desulfovibrio, which was ameliorated by 2'‐FL treatment. These findings highlight that 2'‐FL is an ideal dietary prebiotic for improving aging‐related metabolic disorders by modulating both the adaptive immune system and the gut microbial profile. [ABSTRACT FROM AUTHOR]

Background: The influence of alcohol intake on metabolic dysfunction‐associated fatty liver disease (MAFLD) development and remission remains unclear; thus, we aimed to investigate their longitudinal associations. Methods: This observational cohort study included 6349 patients who underwent more than two health check‐ups over >2 years between April 2013 and March 2021. Generalized estimation equations were used to analyse the longitudinal associations between changes in alcohol intake and MAFLD according to repeated measures at baseline and the most recent stage. Results: The MAFLD development and remission rates were 20.4 and 5.1 and 9.1 and 4.7% in men and women, respectively. Although alcohol consumption was not a significant factor for MAFLD development, consuming 0.1–69.9 g/week (odds ratio [OR]: 0.672, 95% confidence interval [CI]: 0.469–0.964, p <.05) and ≥280 g/week were significant factors for MAFLD development in males (OR: 1.796, 95% CI: 1.009–3.196, p <.05) and females (OR: 16.74, 95% CI: 3.877–72.24, p <.001). Regardless of quantity and frequency, alcohol consumption was not a significant factor for MAFLD remission. Several noninvasive liver fibrosis scores were significantly associated with alcohol intake quantity and frequency in males with MAFLD development and remission (p <.05). The nonalcoholic fatty liver disease fibrosis score differed significantly between males with and without reduced alcohol intake (p <.05) who showed MAFLD remission. Conclusions: Although the influence of alcohol intake on MAFLD development and remission differed, alcohol consumption was not beneficial for MAFLD remission in either sex. Alcohol intake reduction or cessation is recommended to prevent liver fibrosis, even in those who achieve MAFLD remission. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction is commonly observed in schizophrenia spectrum disorders (SSDs). The causes of metabolic comorbidity in SSDs are complex and include intrinsic or biological factors linked to the disorder, which are compounded by antipsychotic (AP) medications. The exact mechanisms underlying SSD pathophysiology and AP-induced metabolic dysfunction are unknown, but dysregulated lipid metabolism may play a role. Lipidomics, which detects lipid metabolites in a biological sample, represents an analytical tool to examine lipid metabolism. This systematic review aims to determine peripheral lipid signatures that are dysregulated among individuals with SSDs (1) with minimal exposure to APs and (2) during AP treatment. To accomplish this goal, we searched MEDLINE, Embase, and PsychINFO databases in February 2024 to identify all full-text articles written in English where the authors conducted lipidomics in SSDs. Lipid signatures reported to significantly differ in SSDs compared to controls or in relation to AP treatment and the direction of dysregulation were extracted as outcomes. We identified 46 studies that met our inclusion criteria. Most of the lipid metabolites that significantly differed in minimally AP-treated patients vs. controls comprised glycerophospholipids, which were mostly downregulated. In the AP-treated group vs. controls, the significantly different metabolites were primarily fatty acyls, which were dysregulated in conflicting directions between studies. In the pre-to-post AP-treated patients, the most impacted metabolites were glycerophospholipids and fatty acyls, which were found to be primarily upregulated and conflicting, respectively. These lipid metabolites may contribute to SSD pathophysiology and metabolic dysfunction through various mechanisms, including the modulation of inflammation, cellular membrane permeability, and metabolic signaling pathways. [ABSTRACT FROM AUTHOR]

BackgroundThe rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has led to an increased occurrence of steatotic liver grafts (SLG) in liver transplantation (LT). However, the implications of SLG on post-transplant de novo hepatic steatosis (PTHS) and advanced fibrosis (≥F3) remain uncertain. This study aimed to characterize PTHS and ≥ F3 using magnetic resonance imaging (MRI) in patients who underwent LT for non-MASLD indications and to examine their relationship with SLG.MethodsPost-LT patients with implant biopsy fat content data were recruited for MRI assessments. MRI-proton density fat fraction (MRI-PDFF) and MR elastography (MRE) were performed using a 1.5 Tesla Optima 450 W MR scanner with a 3D volumetric sequence. PTHS and ≥ F3 were defined as MRI-PDFF ≥5% and MRE ≥3.64 kPa, respectively. SLG was defined as implant biopsy fat content ≥5%.ResultsA total of 292 patients (70.5% men, median age at LT: 51.9 years, 22.6% with SLG) were recruited. The majority (73.6%) were transplanted for hepatitis B virus (HBV)-related complications. MRI performed at a median of 12.2 years post-LT identified PTHS in 27.4 and 10.6% of patients. PTHS was independently associated with SLG (OR 2.067, 95% CI 1.082–3.951), central obesity (OR 3.952, 95% CI 1.768–8.832), and hypertension (OR 2.510, 95% CI 1.268–4.966). In contrast, ≥F3 was associated with sex, change in BMI, and abnormal liver biochemistry but not with PTHS or SLG.ConclusionMRI identified a high prevalence of PTHS, which was associated with SLG and metabolic risk factors among Chinese patients transplanted for non-MASLD indications. Advanced graft fibrosis was not associated with PTHS or SLG.

Obesity is a major modifiable risk factor leading to neuroinflammation and neurodegeneration. Excessive fat storage in obesity promotes the progressive infiltration of immune cells into adipose tissue, resulting in the release of pro-inflammatory factors such as cytokines and adipokines. These inflammatory mediators circulate through the bloodstream, propagating inflammation both in the periphery and in the central nervous system. Gut dysbiosis, which results in a leaky intestinal barrier, exacerbates inflammation and plays a significant role in linking obesity to the pathogenesis of neuroinflammation and neurodegeneration through the gut-brain/gut-brain-liver axis. Inflammatory states within the brain can lead to insulin resistance, mitochondrial dysfunction, autolysosomal dysfunction, and increased oxidative stress. These disruptions impair normal neuronal function and subsequently lead to cognitive decline and motor deficits, similar to the pathologies observed in major neurodegenerative diseases, including Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. Understanding the underlying disease mechanisms is crucial for developing therapeutic strategies to address defects in these inflammatory and metabolic pathways. In this review, we summarize and provide insights into different therapeutic strategies, including methods to alter gut dysbiosis, lifestyle changes, dietary supplementation, as well as pharmacological agents derived from natural sources, that target obesity-induced neuroinflammation and neurodegeneration.

BackgroundMetabolic-associated steatohepatitis and liver fibrosis (MASLD) is a growing public health concern, with environmental factors potentially playing a role in its development. This study aimed to investigate the associations between serum cadmium and mercury levels and the risk of MASLD in a nationally representative sample from the United States.MethodsData from the National Health and Nutrition Examination Survey from 1999 to 2018 were analyzed. Serum cadmium and mercury concentrations were measured, and MASLD was defined based on established criteria. Logistic regression models were used to assess the associations between serum metal levels and MASLD, with adjustments for potential confounders. Stratified analyses and restricted cubic spline curves were employed to examine subgroup differences and nonlinear relationships.ResultsThe study revealed significant inverse associations between serum cadmium and mercury levels and the likelihood of MASLD. Individuals in the highest quartiles of cadmium and mercury had lower odds of MASLD compared to those in the lowest quartiles (Model 3: Cadmium Q4 vs. Q1, Mercury Q4 vs. Q1). Stratified analyses showed stronger inverse associations in older adults, males, and never smokers for cadmium, and in females and individuals without diabetes for mercury. Nonlinear dose–response curves indicated critical thresholds beyond which the risk dynamics changed.ConclusionHigher serum levels of cadmium and mercury were associated with a lower risk of MASLD, with notable variations across subgroups. These findings challenge the conventional understanding of these heavy metals as universally harmful and highlight the need for further research to unravel the complex interplay between environmental exposures and MASLD pathophysiology.