RESUMEN
Obesity is associated with metabolic inflammation, which can contribute to insulin resistance, higher blood glucose, and higher insulin indicative of prediabetes progression. The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a metabolic danger sensor implicated in metabolic inflammation. Many features of metabolic disease can activate the NLRP3 inflammasome; however, it is not yet clear which upstream triggers to target, and there are no clinically approved NLRP3 inflammasome inhibitors for metabolic disease. Bruton's tyrosine kinase (BTK) mediates activation of the NLRP3 inflammasome. Ibrutinib is the most-studied pharmacological inhibitor of BTK, and it can improve blood glucose control in obese mice. However, inhibitors of tyrosine kinases are permissive, and it is unknown if BTK inhibitors require BTK to alter endocrine control of metabolism or metabolic inflammation. We tested whether ibrutinib and acalabrutinib, a new generation BTK inhibitor with higher selectivity, require BTK to inhibit the NLRP3 inflammasome, metabolic inflammation, and blood glucose in obese mice. Chronic ibrutinib administration lowered fasting blood glucose and improved glycemia, whereas acalabrutinib increased fasting insulin levels and increased markers of insulin resistance in high-fat diet-fed CBA/J mice with intact Btk. These metabolic effects of BTK inhibitors were absent in CBA/CaHN-Btkxid/J mice with mutant Btk. However, ibrutinib and acalabrutinib reduced NF-κB activity, proinflammatory gene expression, and NLRP3 inflammasome activation in macrophages with and without functional BTK. These data highlight that the BTK inhibitors can have divergent effects on metabolism and separate effects on metabolic inflammation that can occur independently of actions on BTK.NEW & NOTEWORTHY Bruton's tyrosine kinase (BTK) is involved in immune function. It was thought that BTK inhibitors improve characteristics of obesity-related metabolic disease by lowering metabolic inflammation. However, tyrosine kinase inhibitors are permissive, and it was not known if different BTK inhibitors alter host metabolism or immunity through actions on BTK. We found that two BTK inhibitors had divergent effects on blood glucose and insulin via BTK, but inhibition of metabolic inflammation occurred independently of BTK in obese mice.
Asunto(s)
Adenina , Agammaglobulinemia Tirosina Quinasa , Glucemia , Inflamación , Insulina , Proteína con Dominio Pirina 3 de la Familia NLR , Obesidad , Piperidinas , Inhibidores de Proteínas Quinasas , Animales , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Ratones , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Insulina/metabolismo , Insulina/sangre , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Adenina/análogos & derivados , Adenina/farmacología , Piperidinas/farmacología , Piperidinas/uso terapéutico , Inflamación/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Masculino , Ratones Obesos , Benzamidas/farmacología , Benzamidas/uso terapéutico , Resistencia a la Insulina , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Pirazinas/farmacología , Pirazinas/uso terapéutico , Ratones Endogámicos C57BL , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Pirazoles/farmacología , Pirazoles/uso terapéutico , Dieta Alta en Grasa , Ratones NoqueadosRESUMEN
Gut microbiota influence host immunity and metabolism during obesity. Bacterial sensors of the innate immune system relay signals from specific bacterial components (i.e., postbiotics) that can have opposing outcomes on host metabolic inflammation. NOD-like receptors (NLRs) such as Nod1 and Nod2 both recruit receptor-interacting protein kinase 2 (RIPK2) but have opposite effects on blood glucose control. Nod1 connects bacterial cell wall-derived signals to metabolic inflammation and insulin resistance, whereas Nod2 can promote immune tolerance, insulin sensitivity, and better blood glucose control during obesity. NLR family pyrin domain containing (NLRP) inflammasomes can also generate divergent metabolic outcomes. NLRP1 protects against obesity and metabolic inflammation potentially because of a bias toward IL-18 regulation, whereas NLRP3 appears to have a bias toward IL-1ß-mediated metabolic inflammation and insulin resistance. Targeting specific postbiotics that improve immunometabolism is a key goal. The Nod2 ligand, muramyl dipeptide (MDP) is a short-acting insulin sensitizer during obesity or during inflammatory lipopolysaccharide (LPS) stress. LPS with underacylated lipid-A antagonizes TLR4 and counteracts the metabolic effects of inflammatory LPS. Providing underacylated LPS derived from Rhodobacter sphaeroides improved insulin sensitivity in obese mice. Therefore, certain types of LPS can generate metabolically beneficial metabolic endotoxemia. Engaging protective adaptive immunoglobulin immune responses can also improve blood glucose during obesity. A bacterial vaccine approach using an extract of the entire bacterial community in the upper gut promotes protective adaptive immune response and long-lasting improvements in blood glucose control. A key future goal is to identify and combine postbiotics that cooperate to improve blood glucose control.
Asunto(s)
Diabetes Mellitus , Resistencia a la Insulina , Microbiota , Animales , Ratones , Lipopolisacáridos , Proteínas NLR , Inflamación , Obesidad/metabolismoRESUMEN
The aim of this study was to isolate, characterize, and verify possible antibacterial and hemolytic activity for a lectin found in the seeds of Sterculia foetida L. Purification of the lectin from S. foetida (SFL) was realized with ion exchange chromatography DEAE-Sephacel coupled to HPLC. The purity and the molecular weight was determined by SDS-PAGE. The isolated SFL was characterized as to its glycoprotein nature, and sugar specificity, as well as resistance to pH, temperature, denaturing agents, reduction, oxidation, and chelation. A microdilution method was used to determine antibacterial activity, and hemolytic activity was observed in human erythrocytes. The SFL has a molecular weight of 17 kDa, and a carbohydrate content of 53 µg/mL, specific for arabinose and xylose, and is resistant to treatment with urea, sensitive to treatment with sodium metaperiodate and ß-mercaptoethanol, and in the presence of EDTA lost its hemagglutinating activity (HA). However, in the presence of divalent cations (Ca(2 +) and Mn(2 +)) the HA was increased. The SFL remained active even after incubation at 80 °C, and, within pH values of between 5 and 11. The SFL inhibited the bacterial growth of all the tested strains and caused little hemolysis in human erythrocytes when compared to the positive control Triton X-100.