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1.
Cell ; 185(19): 3501-3519.e20, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36041436

RESUMO

How intestinal microbes regulate metabolic syndrome is incompletely understood. We show that intestinal microbiota protects against development of obesity, metabolic syndrome, and pre-diabetic phenotypes by inducing commensal-specific Th17 cells. High-fat, high-sugar diet promoted metabolic disease by depleting Th17-inducing microbes, and recovery of commensal Th17 cells restored protection. Microbiota-induced Th17 cells afforded protection by regulating lipid absorption across intestinal epithelium in an IL-17-dependent manner. Diet-induced loss of protective Th17 cells was mediated by the presence of sugar. Eliminating sugar from high-fat diets protected mice from obesity and metabolic syndrome in a manner dependent on commensal-specific Th17 cells. Sugar and ILC3 promoted outgrowth of Faecalibaculum rodentium that displaced Th17-inducing microbiota. These results define dietary and microbiota factors posing risk for metabolic syndrome. They also define a microbiota-dependent mechanism for immuno-pathogenicity of dietary sugar and highlight an elaborate interaction between diet, microbiota, and intestinal immunity in regulation of metabolic disorders.


Assuntos
Síndrome Metabólica , Microbiota , Animais , Dieta Hiperlipídica , Açúcares da Dieta , Interleucina-17 , Mucosa Intestinal , Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Obesidade , Células Th17
2.
Cell ; 181(6): 1207-1217, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32531244

RESUMO

Alzheimer's disease, obesity-related metabolic syndrome, and cancer are the leading causes of death and among the most costly medical conditions in the Western world. In all three cases, recent discoveries establish the TREM2 receptor as a major pathology-induced immune signaling hub that senses tissue damage and activates robust immune remodeling in response to it. In this review, we summarize and question what is known and remains to be discovered about TREM2 signaling pathway, track the consequences of its activation in physiological niches and pathological contexts, and highlight the promising potential of therapeutic manipulation of TREM2 signaling.


Assuntos
Glicoproteínas de Membrana/metabolismo , Transdução de Sinais/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Humanos , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Neoplasias/metabolismo , Neoplasias/patologia
3.
Nat Immunol ; 18(8): 843-850, 2017 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-28722707

RESUMO

Quantitative and qualitative aspects of nutrition have a profound effect on leukocytes and thereby affect proinflammatory carcinogenic effects or anticancer immune responses. As a result, nutrition affects the incidence, natural progression and therapeutic response of malignant diseases, both in humans and in preclinical animal models. Here we discuss the molecular mechanisms through which alimentary cues modulate metabolic, microbial and neuroendocrine circuitries and thus affect the probability of developing premalignant lesions that progress to clinically manifested disease and the response to therapeutic intervention. We examine each of the connections that compose the triangle of nutrition, immunological and inflammatory reactions and cancer while focusing on the mechanistic aspects of these relationships.


Assuntos
Inflamação/imunologia , Síndrome Metabólica/imunologia , Microbiota/imunologia , Neoplasias/imunologia , Obesidade/imunologia , Dieta , Dieta Ocidental , Humanos , Hipernutrição/imunologia , Fatores de Risco , Vitaminas
4.
Cell ; 159(6): 1253-62, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25480291

RESUMO

Normal energy metabolism is characterized by periodic shifts in glucose and fat oxidation, as the mitochondrial machinery responsible for carbon combustion switches freely between alternative fuels according to physiological and nutritional circumstances. These transitions in fuel choice are orchestrated by an intricate network of metabolic and cell signaling events that enable exquisite crosstalk and cooperation between competing substrates to maintain energy and glucose homeostasis. By contrast, obesity-related cardiometabolic diseases are increasingly recognized as disorders of metabolic inflexibility, in which nutrient overload and heightened substrate competition result in mitochondrial indecision, impaired fuel switching, and energy dysregulation. This Perspective offers a speculative view on the molecular origins and pathophysiological consequences of metabolic inflexibility.


Assuntos
Metabolismo Energético , Síndrome Metabólica/metabolismo , Mitocôndrias/metabolismo , Animais , Respiração Celular , Dieta , Glucose/metabolismo , Humanos , Resistência à Insulina , Modelos Biológicos
5.
Nature ; 621(7978): 389-395, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37648852

RESUMO

Insulin resistance is the primary pathophysiology underlying metabolic syndrome and type 2 diabetes1,2. Previous metagenomic studies have described the characteristics of gut microbiota and their roles in metabolizing major nutrients in insulin resistance3-9. In particular, carbohydrate metabolism of commensals has been proposed to contribute up to 10% of the host's overall energy extraction10, thereby playing a role in the pathogenesis of obesity and prediabetes3,4,6. Nevertheless, the underlying mechanism remains unclear. Here we investigate this relationship using a comprehensive multi-omics strategy in humans. We combine unbiased faecal metabolomics with metagenomics, host metabolomics and transcriptomics data to profile the involvement of the microbiome in insulin resistance. These data reveal that faecal carbohydrates, particularly host-accessible monosaccharides, are increased in individuals with insulin resistance and are associated with microbial carbohydrate metabolisms and host inflammatory cytokines. We identify gut bacteria associated with insulin resistance and insulin sensitivity that show a distinct pattern of carbohydrate metabolism, and demonstrate that insulin-sensitivity-associated bacteria ameliorate host phenotypes of insulin resistance in a mouse model. Our study, which provides a comprehensive view of the host-microorganism relationships in insulin resistance, reveals the impact of carbohydrate metabolism by microbiota, suggesting a potential therapeutic target for ameliorating insulin resistance.


Assuntos
Metabolismo dos Carboidratos , Microbioma Gastrointestinal , Resistência à Insulina , Animais , Humanos , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Microbioma Gastrointestinal/fisiologia , Resistência à Insulina/fisiologia , Monossacarídeos/metabolismo , Insulina/metabolismo , Síndrome Metabólica/metabolismo , Fezes/química , Fezes/microbiologia , Metabolômica
6.
EMBO J ; 43(4): 507-532, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38191811

RESUMO

Metabolic syndrome combines major risk factors for cardiovascular disease, making deeper insight into its pathogenesis important. We here explore the mechanistic basis of metabolic syndrome by recruiting an essential patient cohort and performing extensive gene expression profiling. The mitochondrial fatty acid metabolism enzyme acyl-CoA synthetase medium-chain family member 3 (ACSM3) was identified to be significantly lower expressed in the peripheral blood of metabolic syndrome patients. In line, hepatic ACSM3 expression was decreased in mice with metabolic syndrome. Furthermore, Acsm3 knockout mice showed glucose and lipid metabolic abnormalities, and hepatic accumulation of the ACSM3 fatty acid substrate lauric acid. Acsm3 depletion markedly decreased mitochondrial function and stimulated signaling via the p38 MAPK pathway cascade. Consistently, Acsm3 knockout mouse exhibited abnormal mitochondrial morphology, decreased ATP contents, and enhanced ROS levels in their livers. Mechanistically, Acsm3 deficiency, and lauric acid accumulation activated nuclear receptor Hnf4α-p38 MAPK signaling. In line, the p38 inhibitor Adezmapimod effectively rescued the Acsm3 depletion phenotype. Together, these findings show that disease-associated loss of ACSM3 facilitates mitochondrial dysfunction via a lauric acid-HNF4a-p38 MAPK axis, suggesting a novel therapeutic vulnerability in systemic metabolic dysfunction.


Assuntos
Ácidos Láuricos , Síndrome Metabólica , Humanos , Camundongos , Animais , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Fígado/metabolismo , Ácidos Graxos/metabolismo , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Coenzima A Ligases/farmacologia
7.
Nat Immunol ; 17(6): 618-25, 2016 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-27196520

RESUMO

The bidirectional interaction between the immune system and whole-body metabolism has been well recognized for many years. Via effects on adipocytes and hepatocytes, immune cells can modulate whole-body metabolism (in metabolic syndromes such as type 2 diabetes and obesity) and, reciprocally, host nutrition and commensal-microbiota-derived metabolites modulate immunological homeostasis. Studies demonstrating the metabolic similarities of proliferating immune cells and cancer cells have helped give birth to the new field of immunometabolism, which focuses on how the cell-intrinsic metabolic properties of lymphocytes and macrophages can themselves dictate the fate and function of the cells and eventually shape an immune response. We focus on this aspect here, particularly as it relates to regulatory T cells.


Assuntos
Adipócitos/imunologia , Diabetes Mellitus Tipo 2/imunologia , Macrófagos/metabolismo , Síndrome Metabólica/imunologia , Obesidade/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Homeostase , Humanos , Imunidade , Microbiota , Tolerância Periférica
8.
Nat Rev Genet ; 23(1): 40-54, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34522035

RESUMO

Human physiology is likely to have been selected for endurance physical activity. However, modern humans have become largely sedentary, with physical activity becoming a leisure-time pursuit for most. Whereas inactivity is a strong risk factor for disease, regular physical activity reduces the risk of chronic disease and mortality. Although substantial epidemiological evidence supports the beneficial effects of exercise, comparatively little is known about the molecular mechanisms through which these effects operate. Genetic and genomic analyses have identified genetic variation associated with human performance and, together with recent proteomic, metabolomic and multi-omic analyses, are beginning to elucidate the molecular genetic mechanisms underlying the beneficial effects of physical activity on human health.


Assuntos
Exercício Físico/genética , Estudo de Associação Genômica Ampla/métodos , Metabolômica/métodos , Biologia Molecular/métodos , Resistência Física/genética , Proteômica/métodos , Demência/genética , Variação Genética , Humanos , Síndrome Metabólica/genética , Neoplasias/genética , Fatores de Risco
9.
Nat Rev Mol Cell Biol ; 16(6): 345-59, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25970558

RESUMO

Recent advances in mitochondrial biology have revealed the high diversity and complexity of proteolytic enzymes that regulate mitochondrial function. We have classified mitochondrial proteases, or mitoproteases, on the basis of their function and location, and defined the human mitochondrial degradome as the complete set of mitoproteases that are encoded by the human genome. In addition to their nonspecific degradative functions, mitoproteases perform highly regulated proteolytic reactions that are important in mitochondrial function, integrity and homeostasis. These include protein synthesis, quality control, mitochondrial biogenesis and dynamics, mitophagy and apoptosis. Impaired or dysregulated function of mitoproteases is associated with ageing and with many pathological conditions such as neurodegenerative disorders, metabolic syndromes and cancer. A better understanding of the mitochondrial proteolytic landscape and its modulation may contribute to improving human lifespan and 'healthspan'.


Assuntos
Envelhecimento/metabolismo , Síndrome Metabólica/enzimologia , Mitocôndrias/enzimologia , Proteínas Mitocondriais/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/enzimologia , Doenças Neurodegenerativas/enzimologia , Peptídeo Hidrolases/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Animais , Genoma Humano , Humanos , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Mitocôndrias/genética , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Peptídeo Hidrolases/genética , Proteólise
10.
Cell ; 150(3): 470-80, 2012 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-22863002

RESUMO

Many of the immune and metabolic changes occurring during normal pregnancy also describe metabolic syndrome. Gut microbiota can cause symptoms of metabolic syndrome in nonpregnant hosts. Here, to explore their role in pregnancy, we characterized fecal bacteria of 91 pregnant women of varying prepregnancy BMIs and gestational diabetes status and their infants. Similarities between infant-mother microbiotas increased with children's age, and the infant microbiota was unaffected by mother's health status. Gut microbiota changed dramatically from first (T1) to third (T3) trimesters, with vast expansion of diversity between mothers, an overall increase in Proteobacteria and Actinobacteria, and reduced richness. T3 stool showed strongest signs of inflammation and energy loss; however, microbiome gene repertoires were constant between trimesters. When transferred to germ-free mice, T3 microbiota induced greater adiposity and insulin insensitivity compared to T1. Our findings indicate that host-microbial interactions that impact host metabolism can occur and may be beneficial in pregnancy.


Assuntos
Fezes/microbiologia , Trato Gastrointestinal/microbiologia , Metagenoma , Gravidez , Actinobacteria/isolamento & purificação , Animais , Feminino , Vida Livre de Germes , Humanos , Lactente , Síndrome Metabólica/microbiologia , Camundongos , Proteobactérias/isolamento & purificação
11.
PLoS Genet ; 19(10): e1010997, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37871105

RESUMO

Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach.


Assuntos
Síndrome Metabólica , Humanos , Camundongos , Animais , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Epigenômica , Projetos Piloto , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Dieta Hiperlipídica/efeitos adversos , Epigênese Genética
12.
Proc Natl Acad Sci U S A ; 120(1): e2219054120, 2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36574676

RESUMO

Bioprosthetic heart valves (BHV), made from glutaraldehyde-fixed xenografts, are widely used for surgical and transcatheter valve interventions but suffer from limited durability due to structural valve degeneration (SVD). We focused on metabolic syndrome (MetS), a risk factor for SVD and a highly prevalent phenotype in patients affected by valvular heart disease with a well-recognized cluster of comorbidities. Multicenter patient data (N = 251) revealed that patients with MetS were at significantly higher risk of accelerated SVD and required BHV replacement sooner. Using a next-generation proteomics approach, we identified significantly differential proteomes from leaflets of explanted BHV from MetS and non-MetS patients (N = 24). Given the significance of protein infiltration in MetS-induced SVD, we then demonstrated the protective effects of polyoxazoline modification of BHV leaflets to mitigate MetS-induced BHV biomaterial degeneration (calcification, tissue cross-linking, and microstructural changes) in an ex vivo serum model and an in vivo with MetS rat subcutaneous implants.


Assuntos
Bioprótese , Próteses Valvulares Cardíacas , Síndrome Metabólica , Humanos , Animais , Ratos , Síndrome Metabólica/complicações , Valvas Cardíacas , Fatores de Risco , Valva Aórtica/cirurgia
13.
Am J Hum Genet ; 109(1): 66-80, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34995504

RESUMO

Alternate splicing events can create isoforms that alter gene function, and genetic variants associated with alternate gene isoforms may reveal molecular mechanisms of disease. We used subcutaneous adipose tissue of 426 Finnish men from the METSIM study and identified splice junction quantitative trait loci (sQTLs) for 6,077 splice junctions (FDR < 1%). In the same individuals, we detected expression QTLs (eQTLs) for 59,443 exons and 15,397 genes (FDR < 1%). We identified 595 genes with an sQTL and exon eQTL but no gene eQTL, which could indicate potential isoform differences. Of the significant sQTL signals, 2,114 (39.8%) included at least one proxy variant (linkage disequilibrium r2 > 0.8) located within an intron spanned by the splice junction. We identified 203 sQTLs that colocalized with 141 genome-wide association study (GWAS) signals for cardiometabolic traits, including 25 signals for lipid traits, 24 signals for body mass index (BMI), and 12 signals for waist-hip ratio adjusted for BMI. Among all 141 GWAS signals colocalized with an sQTL, we detected 26 that also colocalized with an exon eQTL for an exon skipped by the sQTL splice junction. At a GWAS signal for high-density lipoprotein cholesterol colocalized with an NR1H3 sQTL splice junction, we show that the alternative splice product encodes an NR1H3 transcription factor that lacks a DNA binding domain and fails to activate transcription. Together, these results detect splicing events and candidate mechanisms that may contribute to gene function at GWAS loci.


Assuntos
Processamento Alternativo , Fatores de Risco Cardiometabólico , Regulação da Expressão Gênica , Locos de Características Quantitativas , Característica Quantitativa Herdável , Gordura Subcutânea/metabolismo , Sítios de Ligação , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Biologia Computacional/métodos , Éxons , Finlândia , Genes Reporter , Estudos de Associação Genética , Predisposição Genética para Doença , Genética Populacional , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Receptores X do Fígado/genética , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Anotação de Sequência Molecular , Fenótipo , Isoformas de Proteínas/genética , Sítios de Splice de RNA , Proteínas de Ligação a RNA
14.
Bioinformatics ; 40(Supplement_1): i199-i207, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38940159

RESUMO

MOTIVATION: The emergence of COVID-19 (C19) created incredible worldwide challenges but offers unique opportunities to understand the physiology of its risk factors and their interactions with complex disease conditions, such as metabolic syndrome. To address the challenges of discovering clinically relevant interactions, we employed a unique approach for epidemiological analysis powered by redescription-based topological data analysis (RTDA). RESULTS: Here, RTDA was applied to Explorys data to discover associations among severe C19 and metabolic syndrome. This approach was able to further explore the probative value of drug prescriptions to capture the involvement of RAAS and hypertension with C19, as well as modification of risk factor impact by hyperlipidemia (HL) on severe C19. RTDA found higher-order relationships between RAAS pathway and severe C19 along with demographic variables of age, gender, and comorbidities such as obesity, statin prescriptions, HL, chronic kidney failure, and disproportionately affecting Black individuals. RTDA combined with CuNA (cumulant-based network analysis) yielded a higher-order interaction network derived from cumulants that furthered supported the central role that RAAS plays. TDA techniques can provide a novel outlook beyond typical logistic regressions in epidemiology. From an observational cohort of electronic medical records, it can find out how RAAS drugs interact with comorbidities, such as hypertension and HL, of patients with severe bouts of C19. Where single variable association tests with outcome can struggle, TDA's higher-order interaction network between different variables enables the discovery of the comorbidities of a disease such as C19 work in concert. AVAILABILITY AND IMPLEMENTATION: Code for performing TDA/RTDA is available in https://github.com/IBM/Matilda and code for CuNA can be found in https://github.com/BiomedSciAI/Geno4SD/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
COVID-19 , Hiperlipidemias , Síndrome Metabólica , Sistema Renina-Angiotensina , SARS-CoV-2 , Humanos , Síndrome Metabólica/epidemiologia , COVID-19/epidemiologia , Hiperlipidemias/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Comorbidade , Hipertensão/epidemiologia , Fatores de Risco
15.
Int Immunol ; 36(1): 17-32, 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-37878760

RESUMO

Chronic obstructive pulmonary disease (COPD) is closely related to innate and adaptive inflammatory immune responses. It is increasingly becoming evident that metabolic syndrome (MetS) affects a significant portion of COPD patients. Through this investigation, we identify shared immune-related candidate biological markers. The Weighted Gene Co-Expression Network Analysis (WGCNA) was utilized to reveal the co-expression modules linked to COPD and MetS. The commonly expressed genes in the COPD and MetS were utilized to conduct an enrichment analysis. We adopted machine-learning to screen and validate hub genes. We also assessed the relationship between hub genes and immune cell infiltration in COPD and MetS, respectively. Moreover, associations across hub genes and metabolic pathways were also explored. Finally, we chose a single-cell RNA sequencing (scRNA-seq) dataset to investigate the hub genes and shared mechanisms at the level of the cells. We also applied cell trajectory analysis and cell-cell communication analysis to focus on the vital immune cell we were interested in. As a result, we selected and validated 13 shared hub genes for COPD and MetS. The enrichment analysis and immune infiltration analysis illustrated strong associations between hub genes and immunology. Additionally, we applied metabolic pathway enrichment analysis, indicating the significant role of reactive oxygen species (ROS) in COPD with MetS. Through scRNA-seq analysis, we found that ROS might accumulate the most in the alveolar macrophages. In conclusion, the 13 hub genes related to the immune response and metabolism may serve as diagnostic biomarkers and treatment targets of COPD with MetS.


Assuntos
Síndrome Metabólica , Doença Pulmonar Obstrutiva Crônica , Humanos , Síndrome Metabólica/genética , Espécies Reativas de Oxigênio , Comunicação Celular , Doença Pulmonar Obstrutiva Crônica/genética , Análise de Sequência de RNA
16.
Arterioscler Thromb Vasc Biol ; 44(6): 1346-1364, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38660806

RESUMO

BACKGROUND: Atherosclerosis is the major underlying pathology of cardiovascular disease and is driven by dyslipidemia and inflammation. Inhibition of the immunoproteasome, a proteasome variant that is predominantly expressed by immune cells and plays an important role in antigen presentation, has been shown to have immunosuppressive effects. METHODS: We assessed the effect of ONX-0914, an inhibitor of the immunoproteasomal catalytic subunits LMP7 (proteasome subunit ß5i/large multifunctional peptidase 7) and LMP2 (proteasome subunit ß1i/large multifunctional peptidase 2), on atherosclerosis and metabolism in LDLr-/- and APOE*3-Leiden.CETP mice. RESULTS: ONX-0914 treatment significantly reduced atherosclerosis, reduced dendritic cell and macrophage levels and their activation, as well as the levels of antigen-experienced T cells during early plaque formation, and Th1 cells in advanced atherosclerosis in young and aged mice in various immune compartments. Additionally, ONX-0914 treatment led to a strong reduction in white adipose tissue mass and adipocyte progenitors, which coincided with neutrophil and macrophage accumulation in white adipose tissue. ONX-0914 reduced intestinal triglyceride uptake and gastric emptying, likely contributing to the reduction in white adipose tissue mass, as ONX-0914 did not increase energy expenditure or reduce total food intake. Concomitant with the reduction in white adipose tissue mass upon ONX-0914 treatment, we observed improvements in markers of metabolic syndrome, including lowered plasma triglyceride levels, insulin levels, and fasting blood glucose. CONCLUSIONS: We propose that immunoproteasomal inhibition reduces 3 major causes underlying cardiovascular disease, dyslipidemia, metabolic syndrome, and inflammation and is a new target in drug development for atherosclerosis treatment.


Assuntos
Tecido Adiposo Branco , Aterosclerose , Modelos Animais de Doenças , Síndrome Metabólica , Camundongos Endogâmicos C57BL , Complexo de Endopeptidases do Proteassoma , Receptores de LDL , Animais , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Aterosclerose/genética , Aterosclerose/metabolismo , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/imunologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/patologia , Receptores de LDL/genética , Receptores de LDL/deficiência , Complexo de Endopeptidases do Proteassoma/metabolismo , Masculino , Inibidores de Proteassoma/farmacologia , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Doenças da Aorta/prevenção & controle , Doenças da Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/enzimologia , Doenças da Aorta/imunologia , Doenças da Aorta/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Placa Aterosclerótica , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Camundongos Knockout para ApoE , Camundongos , Metabolismo Energético/efeitos dos fármacos , Oligopeptídeos
17.
Nature ; 566(7742): 115-119, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30700910

RESUMO

The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways1, how our bodies handle nutrients depends on strategically positioned metabolic sensors that link the intrinsic nutritional value of a meal with intermediary metabolism. Here we describe a subset of immune cells-integrin ß7+ natural gut intraepithelial T lymphocytes (natural IELs)-that is dispersed throughout the enterocyte layer of the small intestine and that modulates systemic metabolism. Integrin ß7- mice that lack natural IELs are metabolically hyperactive and, when fed a high-fat and high-sugar diet, are resistant to obesity, hypercholesterolaemia, hypertension, diabetes and atherosclerosis. Furthermore, we show that protection from cardiovascular disease in the absence of natural IELs depends on the enteroendocrine-derived incretin GLP-12, which is normally controlled by IELs through expression of the GLP-1 receptor. In this metabolic control system, IELs modulate enteroendocrine activity by acting as gatekeepers that limit the bioavailability of GLP-1. Although the function of IELs may prove advantageous when food is scarce, present-day overabundance of diets high in fat and sugar renders this metabolic checkpoint detrimental to health.


Assuntos
Doenças Cardiovasculares/metabolismo , Progressão da Doença , Intestino Delgado/citologia , Linfócitos Intraepiteliais/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Modelos Animais de Doenças , Ingestão de Alimentos , Enterócitos/citologia , Enterócitos/metabolismo , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Cadeias beta de Integrinas/genética , Cadeias beta de Integrinas/metabolismo , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Síndrome Metabólica/prevenção & controle , Camundongos
18.
Proc Natl Acad Sci U S A ; 119(44): e2210434119, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36282921

RESUMO

The cJun NH2-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating peroxisome proliferator-activated receptor α (PPARα)-dependent expression of the hepatokine fibroblast growth factor 21 (FGF21). Hepatocyte-specific gene ablation studies demonstrated that the Mapk9 gene (encoding JNK2) plays a key mechanistic role. Mutually exclusive inclusion of exons 7a and 7b yields expression of the isoforms JNK2α and JNK2ß. Here we demonstrate that Fgf21 gene expression and metabolic regulation are primarily regulated by the JNK2α isoform. To identify relevant substrates of JNK2α, we performed a quantitative phosphoproteomic study of livers isolated from control mice, mice with JNK deficiency in hepatocytes, and mice that express only JNK2α or JNK2ß in hepatocytes. We identified the JNK substrate retinoid X receptor α (RXRα) as a protein that exhibited JNK2α-promoted phosphorylation in vivo. RXRα functions as a heterodimeric partner of PPARα and may therefore mediate the effects of JNK2α signaling on Fgf21 expression. To test this hypothesis, we established mice with hepatocyte-specific expression of wild-type or mutated RXRα proteins. We found that the RXRα phosphorylation site Ser260 was required for suppression of Fgf21 gene expression. Collectively, these data establish a JNK-mediated signaling pathway that regulates hepatic Fgf21 expression.


Assuntos
Síndrome Metabólica , PPAR alfa , Animais , Camundongos , Proteínas de Transporte/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Síndrome Metabólica/metabolismo , Camundongos Knockout , Fosforilação , PPAR alfa/genética , PPAR alfa/metabolismo , Receptor X Retinoide alfa/genética , Receptor X Retinoide alfa/metabolismo , MAP Quinase Quinase 4/metabolismo
19.
BMC Bioinformatics ; 25(1): 18, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38212697

RESUMO

BACKGROUND: Metabolic syndrome (MetS) is a cluster of metabolic abnormalities (including obesity, insulin resistance, hypertension, and dyslipidemia), which can be used to identify at-risk populations for diabetes and cardiovascular diseases, the main causes of morbidity and mortality worldwide. The achievement of a simple approach for diagnosing MetS without needing biochemical tests is so valuable. The present study aimed to predict MetS using non-invasive features based on a successful random forest learning algorithm. Also, to deal with the problem of data imbalance that naturally exists in this type of data, the effect of two different data balancing approaches, including the Synthetic Minority Over-sampling Technique (SMOTE) and Random Splitting data balancing (SplitBal), on model performance is investigated. RESULTS: The most important determinant for MetS prediction was waist circumference. Applying a random forest learning algorithm to imbalanced data, the trained models reach 86.9% and 79.4% accuracies and 37.1% and 38.2% sensitivities in men and women, respectively. However, by applying the SplitBal data balancing technique, the best results were obtained, and despite that the accuracy of the trained models decreased by 7.8% and 11.3%, but their sensitivity improved significantly to 82.3% and 73.7% in men and women, respectively. CONCLUSIONS: The random forest learning method, along with data balancing techniques, especially SplitBal, could create MetS prediction models with promising results that can be applied as a useful prognostic tool in health screening programs.


Assuntos
Resistência à Insulina , Síndrome Metabólica , Masculino , Humanos , Feminino , Síndrome Metabólica/diagnóstico , Algoritmo Florestas Aleatórias , Fatores de Risco , Obesidade
20.
J Lipid Res ; 65(3): 100519, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38354857

RESUMO

Metabolic syndrome affects more than one in three adults and is associated with increased risk of diabetes, cardiovascular disease, and all-cause mortality. Muscle insulin resistance is a major contributor to the development of the metabolic syndrome. Studies in mice have linked skeletal muscle sarcoplasmic reticulum (SR) phospholipid composition to sarcoplasmic/endoplasmic reticulum Ca2+-ATPase activity and insulin sensitivity. To determine if the presence of metabolic syndrome alters specific phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species in human SR, we compared SR phospholipid composition in skeletal muscle from sedentary subjects with metabolic syndrome and sedentary control subjects without metabolic syndrome. Both total PC and total PE were significantly decreased in skeletal muscle SR of sedentary metabolic syndrome patients compared with sedentary controls, particularly in female participants, but there was no difference in the PC:PE ratio between groups. Total SR PC levels, but not total SR PE levels or PC:PE ratio, were significantly negatively correlated with BMI, waist circumference, total fat, visceral adipose tissue, triglycerides, fasting insulin, and homeostatic model assessment for insulin resistance. These findings are consistent with the existence of a relationship between skeletal muscle SR PC content and insulin resistance in humans.


Assuntos
Resistência à Insulina , Síndrome Metabólica , Adulto , Humanos , Feminino , Animais , Camundongos , Retículo Sarcoplasmático/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/metabolismo , Músculo Esquelético/metabolismo , Fosfolipídeos/metabolismo , Fosfatidilcolinas/metabolismo
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