RESUMO
Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood. Using mouse models, we show that interleukin-6 (IL-6) is the dominant cytokine inducible upon acute stress alone. Stress-inducible IL-6 is produced from brown adipocytes in a beta-3-adrenergic-receptor-dependent fashion. During stress, endocrine IL-6 is the required instructive signal for mediating hyperglycemia through hepatic gluconeogenesis, which is necessary for anticipating and fueling "fight or flight" responses. This adaptation comes at the cost of enhancing mortality to a subsequent inflammatory challenge. These findings provide a mechanistic understanding of the ontogeny and adaptive purpose of IL-6 as a bona fide stress hormone coordinating systemic immunometabolic reprogramming. This brain-brown fat-liver axis might provide new insights into brown adipose tissue as a stress-responsive endocrine organ and mechanistic insight into targeting this axis in the treatment of inflammatory and neuropsychiatric diseases.
Assuntos
Tecido Adiposo Marrom/metabolismo , Interleucina-6/metabolismo , Estresse Psicológico , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea , Encéfalo/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Gluconeogênese , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Interleucina-6/sangue , Interleucina-6/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Adrenérgicos beta 3/metabolismo , Receptores de Interleucina-6/metabolismo , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/genéticaRESUMO
In this issue of Cell, Okin and Medzhitov report that sustained inflammation promotes hyperglycemia by targeting the mevalonate pathway. This represents an important step forward in understanding the mechanisms underlying the association between chronic low-grade inflammation and disruption of normal tissue functions in metabolic diseases.
Assuntos
Hiperglicemia/metabolismo , Insulina , Humanos , Inflamação/metabolismo , Doenças Metabólicas , Transdução de SinaisRESUMO
Control of plasma glucose level is essential to organismal survival. Sustained inflammation has been implicated in control of glucose homeostasis in cases of infection, obesity, and type 2 diabetes; however, the precise role of inflammation in these complex disease states remains poorly understood. Here, we find that sustained inflammation results in elevated plasma glucose due to increased hepatic glucose production. We find that sustained inflammation suppresses CYP7A1, leading to accumulation of intermediate metabolites at the branch point of the mevalonate pathway. This results in prenylation of RHOC, which is concomitantly induced by inflammatory cytokines. Subsequent activation of RHO-associated protein kinase results in elevated plasma glucose. These findings uncover an unexpected mechanism by which sustained inflammation alters glucose homeostasis.
Assuntos
Vias Biossintéticas , Hepatite/metabolismo , Hiperglicemia/metabolismo , Ácido Mevalônico/metabolismo , Animais , Glicemia/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Colesterol 7-alfa-Hidroxilase/metabolismo , Jejum/sangue , Lipopolissacarídeos , Camundongos , Camundongos Obesos , Prenilação de Proteína , Transcrição Gênica , Triglicerídeos/sangue , Proteínas ras/metabolismo , Quinases Associadas a rho/metabolismo , Proteína de Ligação a GTP rhoCRESUMO
In this paper, we provide an overview of the evolution of the definition of hyperglycemia during the past century and the alterations in glucose dynamics that cause fasting and postprandial hyperglycemia. We discuss how extensive mechanistic, physiological research into the factors and pathways that regulate the appearance of glucose in the circulation and its uptake and metabolism by tissues and organs has contributed knowledge that has advanced our understanding of different types of hyperglycemia, namely prediabetes and diabetes and their subtypes (impaired fasting plasma glucose, impaired glucose tolerance, combined impaired fasting plasma glucose, impaired glucose tolerance, type 1 diabetes, type 2 diabetes, gestational diabetes mellitus), their relationships with medical complications, and how to prevent and treat hyperglycemia.
Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Hiperglicemia , Estado Pré-Diabético , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glucose , Intolerância à Glucose/metabolismo , Humanos , Hiperglicemia/metabolismo , Estado Pré-Diabético/diagnóstico , Gravidez , AçúcaresRESUMO
A variety of signals finely tune insulin secretion by pancreatic ß cells to prevent both hyper-and hypoglycemic states. Here, we show that post-translational regulation of the transcription factors ETV1, ETV4, and ETV5 by the ubiquitin ligase COP1 (also called RFWD2) in ß cells is critical for insulin secretion. Mice lacking COP1 in ß cells developed diabetes due to insulin granule docking defects that were fully rescued by genetic deletion of Etv1, Etv4, and Etv5. Genes regulated by ETV1, ETV4, or ETV5 in the absence of mouse COP1 were enriched in human diabetes-associated genes, suggesting that they also influence human ß-cell pathophysiology. In normal ß cells, ETV4 was stabilized upon membrane depolarization and limited insulin secretion under hyperglycemic conditions. Collectively, our data reveal that ETVs negatively regulate insulin secretion for the maintenance of normoglycemia.
Assuntos
Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus/metabolismo , Exocitose , Deleção de Genes , Glucose/metabolismo , Humanos , Hiperglicemia/metabolismo , Secreção de Insulina , Camundongos , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/genéticaRESUMO
The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis1. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.
Assuntos
Maleato de Dizocilpina , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Obesidade , Receptores de N-Metil-D-Aspartato , Animais , Humanos , Masculino , Camundongos , Ratos , Tronco Encefálico/metabolismo , Tronco Encefálico/efeitos dos fármacos , Modelos Animais de Doenças , Maleato de Dizocilpina/efeitos adversos , Maleato de Dizocilpina/farmacologia , Maleato de Dizocilpina/uso terapêutico , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ratos Sprague-Dawley , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Vogt et al. demonstrate that, in mice, maternal high-fat feeding during lactation is sufficient to program the offspring for impaired energy and glucose homeostasis throughout their lifetime. They reveal that the resulting abnormal insulin signaling in the offspring interferes with the formation of hypothalamic neural circuits that contribute to metabolic status.
Assuntos
Dieta Hiperlipídica , Hiperglicemia/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Lactação , Obesidade/metabolismo , Animais , Feminino , Masculino , GravidezRESUMO
Maternal metabolic homeostasis exerts long-term effects on the offspring's health outcomes. Here, we demonstrate that maternal high-fat diet (HFD) feeding during lactation predisposes the offspring for obesity and impaired glucose homeostasis in mice, which is associated with an impairment of the hypothalamic melanocortin circuitry. Whereas the number and neuropeptide expression of anorexigenic proopiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP) neurons, electrophysiological properties of POMC neurons, and posttranslational processing of POMC remain unaffected in response to maternal HFD feeding during lactation, the formation of POMC and AgRP projections to hypothalamic target sites is severely impaired. Abrogating insulin action in POMC neurons of the offspring prevents altered POMC projections to the preautonomic paraventricular nucleus of the hypothalamus (PVH), pancreatic parasympathetic innervation, and impaired glucose-stimulated insulin secretion in response to maternal overnutrition. These experiments reveal a critical timing, when altered maternal metabolism disrupts metabolic homeostasis in the offspring via impairing neuronal projections, and show that abnormal insulin signaling contributes to this effect.
Assuntos
Dieta Hiperlipídica , Hiperglicemia/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Lactação , Obesidade/metabolismo , Animais , Axônios/metabolismo , Feminino , Masculino , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Gravidez , Pró-Opiomelanocortina/metabolismo , Receptor de Insulina/metabolismo , Transdução de SinaisRESUMO
People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. 1), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics.
Assuntos
Células Dendríticas , Complicações do Diabetes , Diabetes Mellitus , Suscetibilidade a Doenças , Hiperglicemia , Pulmão , Viroses , Animais , Camundongos , Acetilcoenzima A/metabolismo , Acetilação , Cromatina/genética , Cromatina/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Complicações do Diabetes/imunologia , Complicações do Diabetes/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Histonas/metabolismo , Hiperglicemia/complicações , Hiperglicemia/imunologia , Hiperglicemia/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Linfócitos T/imunologia , Viroses/complicações , Viroses/imunologia , Viroses/mortalidade , Vírus/imunologia , Modelos Animais de Doenças , HumanosRESUMO
Here, we demonstrate that the fractalkine (FKN)/CX3CR1 system represents a regulatory mechanism for pancreatic islet ß cell function and insulin secretion. CX3CR1 knockout (KO) mice exhibited a marked defect in glucose and GLP1-stimulated insulin secretion, and this defect was also observed in vitro in isolated islets from CX3CR1 KO mice. In vivo administration of FKN improved glucose tolerance with an increase in insulin secretion. In vitro treatment of islets with FKN increased intracellular Ca(2+) and potentiated insulin secretion in both mouse and human islets. The KO islets exhibited reduced expression of a set of genes necessary for the fully functional, differentiated ß cell state, whereas treatment of wild-type (WT) islets with FKN led to increased expression of these genes. Lastly, expression of FKN in islets was decreased by aging and high-fat diet/obesity, suggesting that decreased FKN/CX3CR1 signaling could be a mechanism underlying ß cell dysfunction in type 2 diabetes.
Assuntos
Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Receptores de Quimiocinas/metabolismo , Transdução de Sinais , Adulto , Envelhecimento , Animais , Receptor 1 de Quimiocina CX3C , Cadáver , Quimiocina CX3CL1/administração & dosagem , Quimiocina CX3CL1/metabolismo , Dieta Hiperlipídica , Expressão Gênica , Glucose/metabolismo , Humanos , Hiperglicemia/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Receptores de Quimiocinas/genéticaRESUMO
Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated1. Gestational diabetes has profound and enduring effects on the long-term health of the offspring2,3. However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote4, is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene (Gck), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring.
Assuntos
Dioxigenases , Intolerância à Glucose , Hiperglicemia , Oócitos , Adulto , Animais , Dioxigenases/metabolismo , Feminino , Glucose/metabolismo , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Humanos , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperglicemia/metabolismo , Herança Materna , Camundongos , Oócitos/metabolismoRESUMO
The physiological role of immune cells in the regulation of postprandial glucose metabolism has not been fully elucidated. We have found that adipose tissue macrophages produce interleukin-10 (IL-10) upon feeding, which suppresses hepatic glucose production in cooperation with insulin. Both elevated insulin and gut-microbiome-derived lipopolysaccharide in response to feeding are required for IL-10 production via the Akt/mammalian target of rapamycin (mTOR) pathway. Indeed, myeloid-specific knockout of the insulin receptor or bone marrow transplantation of mutant TLR4 marrow cells results in increased expression of gluconeogenic genes and impaired glucose tolerance. Furthermore, myeloid-specific Akt1 and Akt2 knockout results in similar phenotypes that are rescued by additional knockout of TSC2, an inhibitor of mTOR. In obesity, IL-10 production is impaired due to insulin resistance in macrophages, whereas adenovirus-mediated expression of IL-10 ameliorates postprandial hyperglycemia. Thus, the orchestrated response of the endogenous hormone and gut environment to feeding is a key regulator of postprandial glycemia.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Hiperglicemia/patologia , Insulina/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/análise , Gluconeogênese/genética , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina , Interleucina-10/fisiologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Knockout , Período Pós-Prandial , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Proteína 2 do Complexo Esclerose Tuberosa/fisiologiaRESUMO
BACKGROUND: Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise intolerance remains undefined. We recently demonstrated that the interaction between ARRDC4 (arrestin domain-containing protein 4) and GLUT1 (glucose transporter 1) regulates cardiac metabolism. METHODS: To determine whether this mechanism broadly impacts diabetic complications, we investigated the role of ARRDC4 in the pathogenesis of diabetic cardiac/skeletal myopathy using cellular and animal models. RESULTS: High glucose promoted translocation of MondoA into the nucleus, which upregulated Arrdc4 transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of ARRDC4 was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial Arrdc4 expression in multiple types of mouse models of diabetes. We analyzed hyperglycemia-induced cardiac and skeletal muscle abnormalities in insulin-deficient mice. Hyperglycemia increased advanced glycation end-products and elicited oxidative and endoplasmic reticulum stress leading to apoptosis in the heart and peripheral muscle. Deletion of Arrdc4 augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that Arrdc4-knockout mice had greater cardiac inotropic/chronotropic reserve with higher exercise endurance than wild-type animals under diabetes. While multiple organs were involved in the mechanism, cardiac-specific overexpression using an adenoassociated virus suggests that high levels of myocardial ARRDC4 have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the ARRDC4 mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1. CONCLUSIONS: ARRDC4 regulates hyperglycemia-induced toxicities toward cardiac and skeletal muscle, revealing a new molecular framework that connects hyperglycemia to cardiac/skeletal myopathy to exercise intolerance.
Assuntos
Tolerância ao Exercício , Transportador de Glucose Tipo 1 , Camundongos Knockout , Animais , Humanos , Masculino , Camundongos , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/fisiopatologia , Cardiomiopatias Diabéticas/etiologia , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Hiperglicemia/metabolismo , Hiperglicemia/genética , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Miócitos Cardíacos/metabolismoRESUMO
Collateral circulation is essential for blood resupply to the ischemic heart, which is dictated by the contractile phenotypic restoration of vascular smooth muscle cells (VSMC). Here we investigate whether S-nitrosylation of AMP-activated protein kinase (AMPK), a key regulator of the VSMC phenotype, impairs collateral circulation. In rats with collateral growth and development, nitroglycerin decreases coronary collateral blood flow (CCBF), inhibits vascular contractile phenotypic restoration, and increases myocardial infarct size, accompanied by reduced AMPK activity in the collateral zone. Nitric oxide (NO) S-nitrosylates human recombinant AMPKγ1 at cysteine 131 and decreases AMP sensitivity of AMPK. In VSMCs, exogenous expression of S-nitrosylation-resistant AMPKγ1 or deficient NO synthase (iNOS) prevents the disruption of VSMC reprogramming. Finally, hyperhomocysteinemia or hyperglycemia increases AMPKγ1 S-nitrosylation, prevents vascular contractile phenotypic restoration, reduces CCBF, and increases the infarct size of the heart in Apoe-/- mice, all of which is rescued in Apoe-/-/iNOSsm-/- mice or Apoe-/- mice with enforced expression of the AMPKγ1-C130A mutant following RI/MI. We conclude that nitrosative stress disrupts coronary collateral circulation during hyperhomocysteinemia or hyperglycemia through AMPK S-nitrosylation.
Assuntos
Hiperglicemia , Hiper-Homocisteinemia , Ratos , Camundongos , Humanos , Animais , Circulação Colateral , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Músculo Liso Vascular , Hiper-Homocisteinemia/metabolismo , Apolipoproteínas E/metabolismo , Hiperglicemia/metabolismoRESUMO
Emerging evidence indicates that parental diseases can impact the health of subsequent generations through epigenetic inheritance. Recently, it was shown that maternal diabetes alters the metaphase II oocyte transcriptome, causing metabolic dysfunction in offspring. However, type 1 diabetes (T1D) mouse models frequently utilized in previous studies may be subject to several confounding factors due to severe hyperglycemia. This limits clinical translatability given improvements in glycemic control for T1D subjects. Here, we optimize a T1D mouse model to investigate the effects of appropriately managed maternal glycemic levels on oocytes and intrauterine development. We show that diabetic mice with appropriate glycemic control exhibit better long-term health, including maintenance of the oocyte transcriptome and chromatin accessibility. We further show that human oocytes undergoing in vitro maturation challenged with mildly increased levels of glucose, reflecting appropriate glycemic management, also retain their transcriptome. However, fetal growth and placental function are affected in mice despite appropriate glycemic control, suggesting the uterine environment rather than the germline as a pathological factor in developmental programming in appropriately managed diabetes.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Hiperglicemia , Humanos , Feminino , Gravidez , Camundongos , Animais , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Placenta , Hiperglicemia/genética , Hiperglicemia/metabolismo , Oócitos/metabolismo , Modelos Animais de DoençasRESUMO
One of the independent risk factors for atrial fibrillation is diabetes mellitus (DM); however, the underlying mechanisms causing atrial fibrillation in DM are unknown. The underlying mechanism of Atrogin-1-mediated SK2 degradation and associated signaling pathways are unclear. The aim of this study was to elucidate the relationship among reactive oxygen species (ROS), the NF-κB signaling pathway, and Atrogin-1 protein expression in the atrial myocardia of DM mice. We found that SK2 expression was downregulated comitant with increased ROS generation and enhanced NF-κB signaling activation in the atrial cardiomyocytes of DM mice. These observations were mimicked by exogenously applicating H2O2 and by high glucose culture conditions in HL-1 cells. Inhibition of ROS production by diphenyleneiodonium chloride or silencing of NF-κB by siRNA decreased the protein expression of NF-κB and Atrogin-1 and increased that of SK2 in HL-1 cells with high glucose culture. Moreover, chromatin immunoprecipitation assay demonstrated that NF-κB/p65 directly binds to the promoter of the FBXO32 gene (encoding Atrogin-1), regulating the FBXO32 transcription. Finally, we evaluated the therapeutic effects of curcumin, known as a NF-κB inhibitor, on Atrogin-1 and SK2 expression in DM mice and confirmed that oral administration of curcumin for 4 weeks significantly suppressed Atrogin-1 expression and protected SK2 expression against hyperglycemia. In summary, the results from this study indicated that the ROS/NF-κB signaling pathway participates in Atrogin-1-mediated SK2 regulation in the atria of streptozotocin-induced DM mice.
Assuntos
Diabetes Mellitus Experimental , Átrios do Coração , Proteínas Musculares , NF-kappa B , Espécies Reativas de Oxigênio , Proteínas Ligases SKP Culina F-Box , Transdução de Sinais , Canais de Potássio Ativados por Cálcio de Condutância Baixa , Animais , Camundongos , Fibrilação Atrial/etiologia , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Linhagem Celular , Imunoprecipitação da Cromatina , Curcumina/farmacologia , Curcumina/uso terapêutico , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Peróxido de Hidrogênio/farmacologia , Hiperglicemia/genética , Hiperglicemia/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Miocárdio , Miócitos Cardíacos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Proteólise , Espécies Reativas de Oxigênio/metabolismo , RNA Interferente Pequeno , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismoRESUMO
Excessive gluconeogenesis can lead to hyperglycemia and diabetes through as yet incompletely understood mechanisms. Herein, we show that hepatic ZBTB22 expression is increased in both diabetic clinical samples and mice, being affected by nutritional status and hormones. Hepatic ZBTB22 overexpression increases the expression of gluconeogenic and lipogenic genes, heightening glucose output and lipids accumulation in mouse primary hepatocytes (MPHs), while ZBTB22 knockdown elicits opposite effects. Hepatic ZBTB22 overexpression induces glucose intolerance and insulin resistance, accompanied by moderate hepatosteatosis, while ZBTB22-deficient mice display improved energy expenditure, glucose tolerance, and insulin sensitivity, and reduced hepatic steatosis. Moreover, hepatic ZBTB22 knockout beneficially regulates gluconeogenic and lipogenic genes, thereby alleviating glucose intolerance, insulin resistance, and liver steatosis in db/db mice. ZBTB22 directly binds to the promoter region of PCK1 to enhance its expression and increase gluconeogenesis. PCK1 silencing markedly abolishes the effects of ZBTB22 overexpression on glucose and lipid metabolism in both MPHs and mice, along with the corresponding changes in gene expression. In conclusion, targeting hepatic ZBTB22/PEPCK1 provides a potential therapeutic approach for diabetes.
Assuntos
Fígado Gorduroso , Intolerância à Glucose , Hiperglicemia , Resistência à Insulina , Camundongos , Animais , Gluconeogênese/genética , Resistência à Insulina/genética , Fígado/metabolismo , Hiperglicemia/genética , Hiperglicemia/metabolismo , Glucose/metabolismo , Fígado Gorduroso/metabolismo , Camundongos Endogâmicos C57BL , Hepatócitos/metabolismoRESUMO
BACKGROUND: Hyperglycemia-a symptom that characterizes diabetes-is highly associated with atherothrombotic complications. However, the underlying mechanism by which hyperglycemia fuels platelet activation and arterial thrombus formation is still not fully understood. METHODS: The profiles of polyunsaturated fatty acid metabolites in the plasma of patients with diabetes and healthy controls were determined with targeted metabolomics. FeCl3-induced carotid injury model was used to assess arterial thrombus formation in mice with endothelial cell (EC)-specific YAP (yes-associated protein) deletion or overexpression. Flow cytometry and clot retraction assay were used to evaluate platelet activation. RNA sequencing and multiple biochemical analyses were conducted to unravel the underlying mechanism. RESULTS: The plasma PGE2 (prostaglandin E2) concentration was elevated in patients with diabetes with thrombotic complications and positively correlated with platelet activation. The PGE2 synthetases COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E synthase-1) were found to be highly expressed in ECs but not in other type of vessel cells in arteries from both patients with diabetes and hyperglycemic mice, compared with nondiabetic individuals and control mice, respectively. A combination of RNA sequencing and ingenuity pathway analyses indicated the involvement of YAP signaling. EC-specific deletion of YAP limited platelet activation and arterial thrombosis in hyperglycemic mice, whereas EC-specific overexpression of YAP in mice mimicked the prothrombotic state of diabetes, without affecting hemostasis. Mechanistically, we found that hyperglycemia/high glucose-induced endothelial YAP nuclear translocation and subsequently transcriptional expression of COX-2 and mPGES-1 contributed to the elevation of PGE2 and platelet activation. Blockade of EP3 (prostaglandin E receptor 3) activation by oral administration of DG-041 reversed the hyperactivity of platelets and delayed thrombus formation in both EC-specific YAP-overexpressing and hyperglycemic mice. CONCLUSIONS: Collectively, our data suggest that hyperglycemia-induced endothelial YAP activation aggravates platelet activation and arterial thrombus formation via PGE2/EP3 signaling. Targeting EP3 with DG-041 might be therapeutic for diabetes-related thrombosis.
Assuntos
Diabetes Mellitus , Hiperglicemia , Trombose , Animais , Humanos , Camundongos , Plaquetas/metabolismo , Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus/metabolismo , Dinoprostona/metabolismo , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Camundongos Obesos , Trombose/genética , Trombose/metabolismoRESUMO
The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.
Assuntos
Receptor gp130 de Citocina/metabolismo , Citocinas/síntese química , Citocinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Ligação Competitiva , Citocinas/química , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Fármacos , Fígado Gorduroso/prevenção & controle , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Incretinas/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Obesidade/metabolismo , Pâncreas/metabolismo , Fosfoproteínas/metabolismo , Engenharia de Proteínas , Receptores de Interleucina-6/metabolismo , Transdução de Sinais , Fatores de Transcrição , Aumento de Peso/efeitos dos fármacos , Proteínas de Sinalização YAPRESUMO
Diabetes mellitus is on the rise globally and is a known susceptibility factor for severe influenza virus infections. However, the mechanisms by which diabetes increases the severity of an influenza virus infection are yet to be fully defined. Diabetes mellitus is hallmarked by high glucose concentrations in the blood. We hypothesized that these high glucose concentrations affect the functionality of CD8+ T cells, which play a key role eliminating virus-infected cells and have been shown to decrease influenza disease severity. To study the effect of hyperglycemia on CD8+ T cell function, we stimulated peripheral blood mononuclear cells (PBMCs) from donors with and without diabetes with influenza A virus, anti-CD3/anti-CD28-coated beads, PMA and ionomycin (PMA/I), or an influenza viral peptide pool. After stimulation, cells were assessed for functionality [as defined by expression of IFN-γ, TNF-α, macrophage inflammatory protein (MIP)-1ß, and lysosomal-associated membrane protein-1 (CD107a)] using flow cytometry. Our results showed that increasing HbA1c correlated with a reduction in TNF-α production by CD8+ T cells in response to influenza stimulation in a TCR-specific manner. This was not associated with any changes to CD8+ T cell subsets. We conclude that hyperglycemia impairs CD8+ T cell function to influenza virus infection, which may be linked with the increased risk of severe influenza in patients with diabetes.