Metabolic Inflammation Research Articles

Investigating the Impact of IL6 on Insulin Secretion: Evidence from INS-1 Cells, Human Pancreatic Islets, and Serum Analysis

Interleukin-6 (IL6) is a pleiotropic cytokine implicated in metabolic disorders and inflammation, yet its precise influence on insulin secretion and glucose metabolism remains uncertain. This study examined IL6 expression in pancreatic islets from individuals with/without diabetes, alongside a series of functional experiments, including siRNA silencing; IL6 treatment; and assessments of glucose uptake, cell viability, apoptosis, and expression of key β-cell genes, which were conducted in both INS-1 cells and human islets to elucidate the effect of IL6 on insulin secretion. Serum levels of IL6 from Emirati patients with type 2 diabetes (T2D) were measured, and the effect of antidiabetic drugs on IL6 levels was studied. The results revealed that IL6 mRNA expression was higher in islets from diabetic and older donors compared to healthy or young donors. IL6 expression correlated negatively with PDX1, MAFB, and NEUROD1 and positively with SOX4, HES1, and FOXA1. Silencing IL6 in INS-1 cells reduced insulin secretion and glucose uptake independently of apoptosis or oxidative stress. Reduced expression of IL6 was associated with the downregulation of Ins, Pdx1, Neurod1, and Glut2 in INS-1 cells. In contrast, IL6 treatment enhanced insulin secretion in INS-1 cells and human islets and upregulated insulin expression. Serum IL6 levels were elevated in patients with T2D and associated with higher glucose, HbA1c, and triglycerides, regardless of glucose-lowering medications. This study provides a new understanding of the role of IL6 in β-cell function and the pathophysiology of T2D. Our data highlight differences in the response to IL6 between INS-1 cells and human islets, suggesting the presence of species-specific variations across different experimental models. Further research is warranted to unravel the precise mechanisms underlying the observed effects of IL-6 on insulin secretion.

Fumonisins alone or mixed with other fusariotoxins increase the C22–24:C16 sphingolipid ratios in chicken livers, while deoxynivalenol and zearalenone have no effect

Poultry feed is often contaminated with fumonisins, deoxynivalenol, and zearalenone, which can result in oxidative damage, inflammation and change in lipid metabolism. Although sphingolipids play key roles in cells, only the effects of fumonisins on the sphingolipidome are well-documented. In chickens, fumonisins have been shown to increase the sphinganine to sphingosine ratio and the C22-24:C16 sphingolipid ratio, which has been proposed as a new biomarker of toxicity. In this study, we used UHPLC-MSMS targeted analysis to measure the effect of fusariotoxins on sphingolipids in the livers of chickens fed with diets containing fusariotoxins administered individually and in combination, at the maximum levels recommended by the European Commission. Chickens were exposed from hatching until they reached 35 days of age. This study revealed for the first time that fumonisins, deoxynivalenol, and zearalenone alone and in combination have numerous effects on the sphingolipidome in chicken livers. A 30–50 % decrease in ceramide, dihydroceramide, sphingomyelin, dihydrosphingomyelin, monohexosylceramide and lactosylceramide measured at the class level was observed when fusariotoxins were administered alone, whereas a 30–100 % increase in dihydroceramide, sphingomyelin, dihydrosphingomyelin, and monohexosylceramide was observed when the fusariotoxins were administered in combination. For these different variables, strong significant interactions were observed between fumonisins and zearalenone and between fumonisins and deoxynivalenol, whereas interactions between deoxynivalenol and zearalenone were less frequent and less significant. Interestingly, an increase in the C22-24:C16 ratio of ceramides, sphingomyelins, and monohexosylceramides was observed in chickens fed the diets containing fumonisins only, and this increase was close when the toxin was administered alone or in combination with deoxynivalenol and zearalenone. This effect mainly corresponded to a decrease in sphingolipids with a fatty acid chain length of 16 carbons, whereas C22-24 sphingolipids were unaffected or increased. In conclusion the C22-24:C16 ratio emerged as a specific biomarker, with variations dependent only on the presence of fumonisins.

Associations of sex hormone ratios with metabolic syndrome and inflammation in US adult men and women.

Sex hormones play a critical role in sex differences and cardiovascular disease risk associated with metabolic syndrome (MS) and inflammation. However, the associations of sex hormone ratios with metabolic and inflammatory markers are unclear according to sex and age differences. We evaluated the associations of sex hormone ratios with MS and inflammation among males and females. A retrospective cross-sectional study was conducted by including all adults from the National Health and Nutrition Examination Survey cycles 2013-2016 and excluding any pregnant women, heart disease, diabetes, and those currently taking insulin. MS was defined using the National Cholesterol Education Program criteria and a high-sensitivity C-reactive protein (CRP) level>3 mg/L was defined as a high CRP. Measures of MS components and CRP concentrations were also analyzed. The primary exposures were testosterone to estradiol (excess androgen index), testosterone to sex hormone-binding globulin (free androgen index), and estradiol to sex hormone-binding globulin (free estradiol index). The adjusted associations were summarized with a relative risk (RR) and 95% confidence interval (CI). This study included 9167 subjects with 4360 males and 4807 females. Increases in free estradiol index were positively associated with MS (RR=1.48; 95%CI: 1.39, 1.58; RR=1.31; 95%CI: 1.22, 1.40) and high CRP (RR=1.49; 95%CI: 1.25, 1.77; RR=1.26; 95%CI: 1.06, 1.50) in men with age<50 years and age≥50 years, respectively. Similarly, higher free estradiol index was also robustly associated with increased prevalence of MS (RR=1.22; 95%CI: 1.15, 1.28) and high CRP (RR=1.68; 95%CI: 1.48, 1.90) in women with age ≥50 years. Among women with age<50 years, a higher free androgen index was associated with MS (RR=1.34; 95%CI: 1.25, 1.42) and high CRP (RR=1.13; 95%CI: 1.02, 1.25). These associations were unchanged even after adjusting for all sex hormones. Free estradiol index was consistently and positively associated with MS and high CRP in males of all ages and older females. Free androgen index was positively associated with MS and high CRP in females with age<50 years.

Bazi Bushen ameliorates age-related energy metabolism dysregulation by targeting the IL-17/TNF inflammatory pathway associated with SASP

BackgroundChronic inflammation and metabolic dysfunction are key features of systemic aging, closely associated with the development and progression of age-related metabolic diseases. Bazi Bushen (BZBS), a traditional Chinese medicine used to alleviate frailty, delays biological aging by modulating DNA methylation levels. However, the precise mechanism of its anti-aging effect remains unclear. In this study, we developed the Energy Expenditure Aging Index (EEAI) to estimate biological age. By integrating the EEAI with transcriptome analysis, we aimed to explore the impact of BZBS on age-related metabolic dysregulation and inflammation in naturally aging mice.MethodsWe conducted indirect calorimetry analysis on five groups of mice with different ages and utilized the data to construct EEAI. 12 -month-old C57BL/6 J mice were treated with BZBS or β-Nicotinamide Mononucleotide (NMN) for 8 months. Micro-CT, Oil Red O staining, indirect calorimetry, RNA sequencing, bioinformatics analysis, and qRT-PCR were performed to investigate the regulatory effects of BZBS on energy metabolism, glycolipid metabolism, and inflammaging.ResultsThe results revealed that BZBS treatment effectively reversed the age-related decline in energy expenditure and enhanced overall metabolism, as indicated by the aging index of energy expenditure derived from energy metabolism parameters across various ages. Subsequent investigations showed that BZBS reduced age-induced visceral fat accumulation and hepatic lipid droplet aggregation. Transcriptomic analysis of perirenal fat and liver indicated that BZBS effectively enhanced lipid metabolism pathways, such as the PPAR signaling pathway, fatty acid oxidation, and cholesterol metabolism, and improved glycolysis and mitochondrial respiration. Additionally, there was a significant improvement in inhibiting the inflammation-related arachidonic acid-linoleic acid metabolism pathway and restraining the IL-17 and TNF inflammatory pathways activated via senescence associated secretory phenotype (SASP).ConclusionsBZBS has the potential to alleviate inflammation in metabolic organs of naturally aged mice and maintain metabolic homeostasis. This study presents novel clinical therapeutic approaches for the prevention and treatment of age-related metabolic diseases.

Appetite sensation improvement by synbiotic supplementation in patients with metabolic syndrome: A randomized controlled clinical trial.

The potential link between dysbiosis, features of metabolic syndrome (MetS), inflammation, and sensation impairment has been recently recognized. However, in this context, there are few indications available regarding the effects of co-supplementation with Bacillus indicus, Bacillus coagulans, and fructooligosaccharide (FOS) prebiotics on patients with MetS. Therefore, this study aimed to investigate the effects of synbiotic supplementation on glycemic indices, inflammatory biomarkers, and appetite among adults with MetS. This study is a randomized, double-blind, placebo-controlled clinical trial conducted in the Endocrine and Metabolism Research Center outpatient clinic in Isfahan, Iran. Fifty-eight MetS patients were randomly assigned to receive either synbiotics (n = 29) or placebo (n = 29) supplementation twice per day for 8 weeks. Finally, 55 patients were recruited for analyses (28 in the intervention group and 27 in the placebo group). Random permuted blocks and a computer-generated random number table were used for treatment allocation. No adverse effects were reported during the study. There were no significant differences in glycemic indices and inflammatory markers within- and between groups (all p > .05). However, a significant increase in the sensation of fullness was documented in the synbiotic group. In conclusion, the eight-week treatment did not improve glycemic control and inflammatory markers. Nevertheless, it demonstrated potential efficacy in enhancing participants' appetite sensations, warranting further evaluation in longer intervention periods during future clinical trials.

Chronic unpredictable mild stress increases serum aldosterone without affecting corticosterone levels and induces hepatic steatosis and renal injury in young adult male rats.

Stress is often associated with anxiety and depressive symptoms in adolescents. Stress is associated with components of metabolic syndrome and inflammation. The present study hypothesizes that aldosterone, more than corticosterone, promotes chronic stress-hepatic steatosis and fibrosis, as well as renal inflammation and fibrosis in young adult rats. Thirty-two young adult male Wistar rats of 51 days old were divided into four groups (n = 8 per group): Control (C), chronic unpredictable mild stress (CUMS), control plus vehicle (C plus veh), CUMS plus eplerenone, a selective aldosterone blocker (CUMS plus EP). On postnatal day 51, eplerenone was administered orally through a gastric tube two hours before the start of the stress test. The CUMS paradigm was administered once daily at different times, with no repetition of the stressor sequence for four weeks. Renal inflammation and fibrosis were measured, as well as liver glycogen, triacylglycerol, and fibrosis levels. The serum concentrations of corticosterone, aldosterone, sodium, and creatinine were measured in urine and serum. The CUMS group showed a high level of serum aldosterone without affecting the level of corticosterone, increased urinary sodium, tubular atrophy, glomerular sclerosis, the presence of inflammation, and fibrosis, without affecting creatinine, increased glycogen content, triacylglycerol, and moderate fibrosis in the liver, and treatment with eplerenone prevented the inflammation, fibrosis, glycogen, and triacylglycerol. Our results show that chronic stress-induced aldosterone promotes hepatic steatosis and renal injury more than corticosterone. The prevention by eplerenone supports our hypothesis.

An evaluation of a hepatotoxicity risk induced by the microplastic polymethyl methacrylate (PMMA) using HepG2/THP-1 co-culture model

Inappropriate disposal of plastic wastes and their durability in nature cause uncontrolled accumulation of plastic in land/marine ecosystems, also causing destructive effects by bioaccumulating along the food chain. Microplastics may cause chronic inflammation in relation to their permanent structures, especially through oxidative stress and cytotoxic cellular damage, which could increase the risk of cancer development. The accumulation of microplastics in the liver is a major concern, and therefore, the identification of the mechanisms of their hepatotoxic effects is of great importance. Polymethyl methacrylate (PMMA) is a widely used thermoplastic. It has been determined that PMMA disrupts lipid metabolism in the liver in various aquatic organisms and causes reproductive and developmental toxicity. PMMA-induced hepatotoxic effects in humans have not yet been clarified. In our study, the toxic effects of PMMA (in the range of 3–10 μm) on the human liver were investigated using the HepG2/THP-1 macrophage co-culture model, which is a sensitive immune-mediated liver injury model. Cellular uptake of micro-sized PMMA in the cells was done by transmission electron microscopy. Determination of its effects on cell viability and inflammatory response, oxidative stress, along with gene and protein expression levels that play a role in the mechanism pathways underlying the effects were investigated. The results concluded that inflammation, oxidative stress, and disruptions in lipid metabolism should be the focus of attention as important underlying causes of PMMA-induced hepatotoxicity. Our study, which points out the potential adverse effects of microplastics on human health, supports the literature information on the subject.

Regulatory T cells and bioenergetics of peripheral blood mononuclear cells linked to pediatric obesity.

Obesity-associated inflammation drives the development of insulin resistance and type 2 diabetes. We sought to identify associations of circulating regulatory T cells (Treg) with the degree of obesity (eg, body mass index Z-score [BMIz]), insulin resistance (homeostatic model of insulin resistance [HOMA-IR]), and glycemic control (HbA1c) in children and adolescents. We further sought to examine associations among bioenergetics of peripheral blood mononuclear cells (PBMCs) and CD4 T cells and BMIz, HOMA-IR, and HbA1c. A total of 65 children and adolescents between the ages 5 and 17 years were studied. HbA1c and fasting levels of plasma glucose and insulin were measured. We quantified circulating Tregs (CD3+CD4+CD25+CD127-FoxP3+) by flow cytometry, and measured mitochondrial respiration (oxygen consumption rate [OCR]) and glycolysis (extracellular acidification rate [ECAR]) in PBMCs and isolated CD4 T cells by Seahorse extracellular flux analysis. Tregs (% CD4) are negatively associated with BMIz but positively associated with HOMA-IR. In PBMCs, OCR/ECAR (a ratio of mitochondrial respiration to glycolysis) is positively associated with BMIz but negatively associated with HbA1c. In children, Tregs decrease as body mass index increases; however, the metabolic stress and inflammation associated with insulin resistance may induce a compensatory increase in Tregs. The degree of obesity is also associated with a shift away from glycolysis in PBMCs but as HbA1c declines, metabolism shifts back toward glycolysis. Comprehensive metabolic assessment of the immune system is needed to better understand the implications immune cell metabolic alterations in the progression from a healthy insulin-sensitive state toward glucose intolerance in children. This observational study was registered at the ClinicalTrials.gov (NCT03960333, https://clinicaltrials.gov/study/NCT03960333?term=NCT03960333&rank=1).

Palmitoleic Acid Ameliorates Metabolic Disorders and Inflammation by Modulating Gut Microbiota and Serum Metabolites.

Palmitoleic acid (POA) is an omega-7 monounsaturated fattyacid that has been suggested to improve metabolic disorders. However, it remains unclear whether gut microbiota plays a role in the amelioration of metabolic disorders by POA. This study aims to investigate the regulation of POA on metabolism, as well as systemic inflammation in HFD-fed mice from the perspective of serum metabolome and gut microbiome. Thirty-six C57BL/6 male mice are randomly assigned to either a normal chow diet containing 1.9% w/w lard or an HFD containing 20.68% w/w lard or 20.68% w/w sea buckthorn pulp oil for 16 weeks. The study finds that POA significantly attenuated hyperlipidemia, insulin resistance, and inflammation in HFD-fed mice. POA supplementation significantly alters the composition of serum metabolites, particularly lipid metabolites in the glycerophospholipid metabolism pathway. POA obviously increases the abundance of Bifidobacterium and decreases the abundance of Allobaculum. Importantly, the study finds that glycerophosphocholine mediates the effect of Bifidobacterium on LDL-C, sphingomyelin mediates the effect of Bifidobacterium on IL-6, and maslinic acid mediates the effect of Allobaculum on IL-6. The results suggest that exogenous POA can improve metabolic disorders and inflammation in HFD-fed mice, potentially by modulating the serum metabolome and gut microbiome.

PDGFRβ + cell HIF2α is dispensable for white adipose tissue metabolic remodeling and hepatic lipid accumulation in obese mice

BackgroundObesity is associated with extensive white adipose tissue (WAT) expansion and remodeling. Healthy WAT expansion contributes to the maintenance of energy balance in the liver, thereby ameliorating obesity-related hepatic steatosis. Tissue-resident mesenchymal stromal cell populations, including PDGFRβ + perivascular cells, are increasingly recognized pivotal as determinants of the manner in which WAT expands. However, the full array of regulatory factors controlling WAT stromal cell functions remains to be fully elucidated. Hypoxia-inducible factors (HIFs) are critical regulators in WAT stromal cell populations such as adipocyte precursor cells (APCs). It is revealed that HIF1α activation within PDGFRβ + stromal cells results in the suppression of de novo adipogenesis and the promotion of a pro-fibrogenic cellular program in obese animals. However, the role of HIF2α in PDGFRβ + cells remains undetermined in vivo.MethodsNew genetic models were employed in which HIF1α (encoded by the Hif1a gene) and HIF2α (encoded by the Epas1 gene) are selectively inactivated in PDGFRβ + cells in an inducible manner using tamoxifen (TAM). With these models, both in vitro and in vivo functional analysis of PDGFRβ + cells lacking HIF proteins were performed. Additionally, comprehensive metabolic phenotyping in diet-induced mouse models were performed to investigate the roles of PDGFRβ + cell HIF proteins in WAT remodeling, liver energy balance and systemic metabolism.ResultsUnlike HIF1α inactivation, the new findings in this study suggest that inducible ablation of HIF2α in PDGFRβ + cells does not cause apparent effects on WAT expansion induced by obesogenic diet. The adipogenic ability of PDGFRβ + APCs is not significantly altered by genetic HIF2α ablation. Moreover, no difference of key parameters associated with healthy WAT remodeling such as improvements of WAT insulin sensitivity, reduction in metabolic inflammation, as well as changes in liver fat accumulation or systemic glucose metabolism, is detected in PDGFRβ + cell Epas1-deficient mice.ConclusionThe new findings in this study support that, in contrast to HIF1α, PDGFRβ + cell HIF2α appears dispensable for WAT metabolic remodeling and the resulting effects on liver metabolic homeostasis in diet-induced obesity, underscoring the isoform-specific roles of HIFα proteins in the regulation of adipose tissue biology.

Dietary Iron Overload Triggers Hepatic Metabolic Disorders and Inflammation in Laying Hen.

Iron, an essential trace element, is involved in various physiological processes; however, consumption of excessive iron possesses detrimental effects. In practical feed production, the iron content added to feeds often far exceeds the actual demand, resulting in an excess of iron in the body. The liver as a central regulator of iron homeostasis is susceptible to damage caused by disorders in iron metabolism. A model of hepatic iron overload in laying hens was developed in this study by incorporating iron into their diet, and the specific mechanisms underlying iron overload-induced hepatic injury were investigated. Firstly, this study revealed that a high-iron diet resulted in hepatic iron overload, accompanied by impaired liver function. Next, assessment of oxidative stress markers indicated a decrease in activities of T-SOD and CAT, coupled with an increase in MDA content, pointing to the iron-overloaded liver oxidative stress. Thirdly, the impact of iron overload on hepatic glycolipid and bile acid metabolism-related gene expressions were explored, including PPAR-α, GLUT2, and CYP7A1, highlighting disruptions in hepatic metabolism. Subsequently, analyses of inflammation-related genes such as iNOS and IL-1β at both protein and mRNA levels demonstrated the presence of inflammation in the liver under conditions of dietary iron overload. Overall, this study provided comprehensive evidence that dietary iron overload contributed to disorders in glycolipid and bile acid metabolism, accompanied by inflammatory responses in laying hens. Further detailing the specific pathways involved and the implications of these findings could offer valuable insights for future research and practical applications in poultry nutrition.

Abstract 58: Multi-Ancestry Genome-Wide Association Study of Age-at-Onset in Heart Failure

Background: Heart failure (HF) is a life-threatening syndrome with growing impact on the global population. It is estimated that &gt;8 million people in the US will be living with HF by 2030. Aging is a major risk factor for HF. Age-at-onset (AAO) is one of the critical traits in cohort studies of age-related diseases. Large-scale genome-wide association studies (GWAS) of HF AAO can provide insights into genetic effects on disease progression and transitions to severe stages. Methods: The multi-ancestry study consisted of a discovery cohort from the Million Veteran Program (MVP) including 67845, 17687, 4936, and 527 HF patients in European, African, Hispanic, and Asian Americans, respectively. HF AAO was determined by the first HF diagnosis date with a measured left ventricle ejection fraction within 90 days. Within each group, a GWAS of AAO was conducted using common SNPs (minor allele frequency&gt;1%) imputed to the 1000 Genome Project panel, adjusted for sex and top 10 ancestry-specific principal components (PCs) of genome-wide SNPs. A meta-analysis of GWAS summary statistics was performed to identify genome-wide significant (GWS, p&lt;5x10 -8 ) loci. In the replication study, 20453 HF patients of European ancestry from the UK Biobank (UKB) study were identified using HF diagnosis codes extracted from in-patient Hospital Episode Statistics and National Death Registry. The age at the first use of a HF diagnosis code was used to approximate the AAO in the GWAS adjusted for sex and top 10 PCs. The sentinel SNPs of GWS locus from the discovery phase were examined for replication in the UKB cohort. Results: From the multi-ancestry GWAS of HF AAO in MVP, four GWS loci were identified in chromosomes 3 (3:49862418, p=3.41x10 -11 ), 9 (9:22124744, p=1.18x10 -11 ), 15 (15:78868398, p=1.60x10 -9 ) and 19 (19:45411941, p=4.15x10 -38 ). All but the chromosome 19 locus were replicated in the UKB, with the most significant replication in the chromosome 3 locus (p=8.74x10 -5 ). The chromosome 3 locus has been associated with multiple phenotypes including metabolic diseases, inflammation, and lung function. The 9p21 locus is a well-established locus of coronary heart disease, which is a key antecedent of HF. The chromosome 15 locus maps to the CHRNA gene cluster, which is associated with pulmonary function and disease, as well as aging. The chromosome 19 locus is located within the APOE gene, which plays an important role in aging, Alzheimer’s disease, and lipid metabolism. The allelic effects of younger HF AAO are in the same direction of elevated disease risk at corresponding loci (e.g., younger AAO and higher CAD risk for 9p21). Conclusion: The significant genetic associations with AAO of HF revealed the pathways and mechanisms regulating HF progression and transition into clinical stages. They may lead to novel targets for treatment and prevention which could eventually reduce the burden of HF among the aging population in the US.

Alternative polyadenylation regulates the translation of metabolic and inflammation-related proteins in adipose tissue of gestational diabetes mellitus

In gestational diabetes mellitus (GDM), adipose tissue undergoes metabolic disturbances and chronic low-grade inflammation. Alternative polyadenylation (APA) is a post-transcriptional modification mechanism that generates mRNA with variable lengths of 3' untranslated regions (3'UTR), and it is associated with inflammation and metabolism. However, the role of APA in GDM adipose tissue has not been well characterized. In this study, we conducted transcriptomic and proteomic sequencing on subcutaneous and omental adipose tissues from both control and GDM patients. Using Dapars, a novel APA quantitative algorithm, we delineated the APA landscape of adipose tissue, revealing significant 3'UTR elongation of mRNAs in the GDM group. Omental adipose tissue exhibited a significant correlation between elongated 3'UTRs and reduced translation levels of genes related to metabolism and inflammation. Validation experiments in THP-1 derived macrophages (TDMs) demonstrated the impact of APA on translation levels by overexpressing long and short 3'UTR isoforms of a representative gene LRRC25. Additionally, LRRC25 was validated to suppress proinflammatory polarization in TDMs. Further exploration revealed two underexpressed APA trans-acting factors, CSTF3 and PPP1CB, in GDM omental adipose tissue. In conclusion, this study provides preliminary insights into the APA landscape of GDM adipose tissue. Reduced APA regulation in GDM omental adipose tissue may contribute to metabolic disorders and inflammation by downregulating gene translation levels. These findings advance our understanding of the molecular mechanisms underlying GDM-associated adipose tissue changes.

Systemic loss of CD36 aggravates NAFLD-related HCC through MEK1/2-ERK1/2 signaling pathway

Background & aimsCD36, a membrane protein widely present in various tissues, is crucial role in regulating energy metabolism. The rise of HCC as a notable outcome of NAFLD is becoming more apparent. Patients with hereditary CD36 deficiency are at increased risk of NAFLD. However, the impact of CD36 deficiency on NAFLD-HCC remains unclear. MethodsGlobal CD36 knockout mice (CD36KO) and wild type mice (WT) were induced to establish NAFLD-HCC model by N-nitrosodiethylamine (DEN) plus high fat diet (HFD). Transcriptomics was employed to examine genes that were expressed differentially. ResultsCompared to WT mice, CD36KO mice showed more severe HFD-induced liver issues and increased tumor malignancy. The MEK1/2-ERK1/2 pathway activation was detected in the liver tissues of CD36KO mice using RNA sequencing and Western blot analysis. ConclusionSystemic loss of CD36 leaded to the advancement of NAFLD to HCC by causing lipid disorders and metabolic inflammation, a process that involves the activation of MAPK signaling pathway. We found that CD36 contributes significantly to the maintenance of metabolic homeostasis in NAFLD-HCC.

The Impact of Metabolic Memory on Immune Profile in Young Patients with Uncomplicated Type 1 Diabetes.

Metabolic memory refers to the long-term effects of achieving early glycemic control and the adverse implications of high blood glucose levels, including the development and progression of diabetes complications. Our study aimed to investigate whether the phenomenon of metabolic memory plays a role in the immune profile of young patients with uncomplicated type 1 diabetes (T1D). The study group included 67 patients with uncomplicated type 1 diabetes with a mean age of 15.1 ± 2.3 years and a minimum disease duration of 1.2 years. The control group consisted of 27 healthy children and adolescents with a mean age of 15.1 ± 2.3 years. Patients were divided into three groups according to their HbA1c levels at the onset of T1D, and the average HbA1c levels after one and two years of disease duration. The subgroup A1 had the lowest initial HbA1c values, while the subgroup C had the highest initial HbA1c values. Cytokine levels (including TNF-α, IL-35, IL-4, IL-10, IL-18, and IL-12) were measured in all study participants. Our data analysis showed that subgroup A1 was characterized by significantly higher levels of IL-35 and IL-10 compared to all other groups, and significantly higher levels of IL-4 compared to group B. Additionally, a comparative analysis of cytokine levels between the groups of diabetic patients and healthy controls demonstrated that subgroup A1 had significantly higher levels of anti-inflammatory cytokines. The lipid profile was also significantly better in subgroup A1 compared to all other patient groups. Based on our findings, it appears that an inflammatory process, characterized by an imbalance between the pro- and anti-inflammatory cytokines, is associated with poor glycemic control at the onset of diabetes and during the first year of disease duration. These findings also suggest that both metabolic memory and inflammation contribute to the abnormal lipid profile in patients with type 1 diabetes.

The Complex Interplay of Insulin Resistance and Metabolic Inflammation in Transition Dairy Cows.

During the transition period, dairy cows exhibit heightened energy requirements to sustain fetal growth and lactogenesis. The mammary gland and the growing fetus increase their demand for glucose, leading to the mobilization of lipids to support the function of tissues that can use fatty acids as energy substrates. These physiological adaptations lead to negative energy balance, metabolic inflammation, and transient insulin resistance (IR), processes that are part of the normal homeorhetic adaptations related to parturition and subsequent lactation. Insulin resistance is characterized by a reduced biological response of insulin-sensitive tissues to normal physiological concentrations of insulin. Metabolic inflammation is characterized by a chronic, low-level inflammatory state that is strongly associated with metabolic disorders. The relationship between IR and metabolic inflammation in transitioning cows is intricate and mutually influential. On one hand, IR may play a role in the initiation of metabolic inflammation by promoting lipolysis in adipose tissue and increasing the release of free fatty acids. Metabolic inflammation, conversely, triggers inflammatory signaling pathways by pro-inflammatory cytokines, thereby leading to impaired insulin signaling. The interaction of these factors results in a harmful cycle in which IR and metabolic inflammation mutually reinforce each other. This article offers a comprehensive review of recent advancements in the research on IR, metabolic inflammation, and their intricate interrelationship. The text delves into multiple facets of physiological regulation, pathogenesis, and their consequent impacts.

Role of pattern recognition receptors and microbiota-derived ligands in obesity

Obesity is associated with activation of low-grade inflammation in tissues metabolically relevant for the regulation glucose homeostasis. The gut microbiota has been extensively linked to the inflammatory responses observed during obesity emphasizing the interconnection between host immunity and metabolism during obesity. Gut microbiota together with alteration of the gut barrier functions provide a myriad of circulating ligands for the pattern recognition receptors (PRRs) expressed in innate immune cells and nonimmune cells. PRR-dependent signalling drives the expression of a wide range of genes beyond the inflammatory response depending on the specific functions of the targeted cells and on the physiological context. PRRs activation can have opposite effects on host metabolic inflammation. Nucleotide-binding oligomerization domain 1 (NOD1) or NOD-like Receptor pyrin domain containing 3 (NLRP3) activation promote metabolic inflammation and insulin resistance while NOD2 activation improves insulin sensitivity and glucose homeostasis during obesity. Toll-like receptors (TLRs) 2, 4 and 5 also display specific effects on metabolic tissues. TLR5 deficient mice are prone to obesity and inflammation in response to high fat diet, while injection of TLR5 ligand, flagellin, has a protective effect toward diet-induced obesity. To the opposite TLR2 and 4 activations are associated with deleterious metabolic outcome during obesity. TLR4 activation enhances metabolic inflammation and insulin resistance and TLR2 via its activation by molecules derived from the gut microbiota favours the onset of obesity. It is now clear that activation of PRRs by bacterial derived molecules plays a key role in the host metabolic regulation. PRRs are expressed in various cell types complicating the understanding of the mechanisms underlying the relationship between PRRs activation/silencing and metabolic inflammation in obesity context. This review presents an overview of the current understanding of the interrelationship between the gut microbiota and PRRs, with a focus on its consequences for obesity and related metabolic diseases.

Melatonin Improves Glucose Homeostasis and Insulin Sensitivity by Mitigating Inflammation and Activating AMPK Signaling in a Mouse Model of Sleep Fragmentation.

Sleep fragmentation (SF) can increase inflammation and production of reactive oxygen species (ROS), leading to metabolic dysfunction. SF is associated with inflammation of adipose tissue and insulin resistance. Several studies have suggested that melatonin may have beneficial metabolic effects due to activating AMP-activated protein kinase (AMPK). However, it is unclear whether melatonin affects the AMPK signaling pathway in SF-induced metabolic dysfunction. Therefore, we hypothesize that SF induces metabolic impairment and inflammation in white adipose tissue (WAT), as well as altered intracellular homeostasis. We further hypothesize that these conditions could be improved by melatonin treatment. We conducted an experiment using adult male C57BL/6 mice, which were divided into three groups: control, SF, and SF with melatonin treatment (SF+Mel). The SF mice were housed in SF chambers, while the SF+Mel mice received daily oral melatonin. After 12 weeks, glucose tolerance tests, insulin tolerance tests, adipose tissue inflammation tests, and AMPK assessments were performed. The SF mice showed increased weight gain, impaired glucose regulation, inflammation, and decreased AMPK in WAT compared to the controls. Melatonin significantly improved these outcomes by mitigating SF-induced metabolic dysfunction, inflammation, and AMPK downregulation in adipose tissue. The therapeutic efficacy of melatonin against cardiometabolic impairments in SF may be due to its ability to restore adipose tissue homeostatic pathways.

Cardiometabolic biomarker patterns associated with cardiac MRI defined fibrosis and microvascular dysfunction in patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a complex disease process influenced by metabolic disorders, systemic inflammation, myocardial fibrosis, and microvascular dysfunction. The goal of our study is to identify potential relationships between plasma biomarkers and cardiac magnetic resonance (CMR) imaging markers in patients with HFpEF. Nineteen subjects with HFpEF and 15 age-matched healthy controls were enrolled and underwent multiparametric CMR and plasma biomarker analysis using the Olink® Cardiometabolic Panel (Olink Proteomics, Uppsala, Sweden). Partial least squares discriminant analysis (PLS-DA) was used to characterize CMR and biomarker variables that differentiate the subject groups into two principal components. Orthogonal projection to latent structures by partial least squares (OPLS) analysis was used to identify biomarker patterns that correlate with myocardial perfusion reserve (MPR) and extracellular volume (ECV) mapping. A PLS-DA could differentiate between HFpEF and normal controls with two significant components explaining 79% (Q2 = 0.47) of the differences. For OPLS, there were 7 biomarkers that significantly correlated with ECV (R2 = 0.85, Q = 0.53) and 6 biomarkers that significantly correlated with MPR (R2 = 0.92, Q2 = 0.32). Only 1 biomarker significantly correlated with both ECV and MPR. Patients with HFpEF have unique imaging and biomarker patterns that suggest mechanisms associated with metabolic disease, inflammation, fibrosis and microvascular dysfunction.

The role of 27-hydroxycholesterol in meta-inflammation.

27-Hydroxycholesterol (27OHChol), a prominent cholesterol metabolite present in the bloodstream and peripheral tissues, is a kind of immune oxysterol that elicits immune response. Recent research indicates the involvement of 27OHChol in metabolic inflammation (meta-inflammation) characterized by chronic responses associated with metabolic irregularities. 27OHChol activates monocytic cells such that they secrete pro-inflammatory cytokines and chemokines, and increase the expression of cell surface molecules such as pattern-recognition receptors that play key roles in immune cell-cell communication and sensing metabolism-associated danger signals. Levels of 27OHChol increase when cholesterol metabolism is disrupted, and the resulting inflammatory responses can contribute to the development and complications of metabolic syndrome, including obesity, insulin resistance, and cardiovascular diseases. Since 27OHChol can induce chronic immune response by activating monocyte-macrophage lineage cells that play a crucial role in meta-inflammation, it is essential to understand the 27OHChol-induced inflammatory responses to unravel the roles and mechanisms of action of this cholesterol metabolite in chronic metabolic disorders.