布鲁顿酪氨酸激酶(BTK)抑制剂会改变肥胖小鼠的血糖和胰岛素,但会减轻炎症,而与 BTK 无关。

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Darryl Y Chan, Nicole G Barra, Han Fang, Rodrigo Rodrigues E-Lacerda, Jonathan D Schertzer
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引用次数: 0

摘要

肥胖与代谢性炎症有关,代谢性炎症可导致胰岛素抵抗、血糖升高和胰岛素升高,而胰岛素升高和胰岛素升高是糖尿病前期发展的征兆。核苷酸结合寡聚化结构域样受体家族含吡啶结构域的 3(NLRP3)炎性体是一种代谢危险传感器,与代谢炎症有牵连。代谢性疾病的许多特征都能激活 NLRP3 炎症小体;然而,目前还不清楚要针对哪种上游触发因素,也没有临床批准的 NLRP3 炎症小体抑制剂可用于代谢性疾病。布鲁顿酪氨酸激酶(BTK)介导 NLRP3 炎症小体的激活。伊布替尼是研究最多的 BTK 药理抑制剂,它可以改善肥胖小鼠的血糖控制。然而,酪氨酸激酶抑制剂是允许性的,BTK抑制剂是否需要BTK来改变代谢或代谢炎症的内分泌控制尚不清楚。我们测试了伊布替尼和具有更高选择性的新一代BTK抑制剂acalabrutinib是否需要BTK来抑制肥胖小鼠的NLRP3炎症组、代谢炎症和血糖。长期服用伊布替尼能降低空腹血糖并改善血糖,而阿卡布替尼则能提高高脂喂养的 CBA/J 小鼠的血胰岛素水平并增加胰岛素抵抗的标志物。BTK抑制剂对Btk突变的CBA/CaHN-Btkxid/J小鼠没有这些代谢影响。然而,伊布替尼和阿卡布替尼降低了具有和不具有功能性 BTK 的巨噬细胞中 NF-κB 活性促炎基因的表达和 NLRP3 炎性体的激活。这些数据突显了 BTK 抑制剂对新陈代谢的不同影响,以及对代谢性炎症的不同影响,这些影响可能独立于对 BTK 的作用而发生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Bruton's tyrosine kinase (BTK) inhibitors alter blood glucose and insulin in obese mice but reduce inflammation independent of BTK.

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.

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来源期刊
CiteScore
9.80
自引率
0.00%
发文量
98
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
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