Ponatinib modulates the metabolic profile of obese mice by inhibiting adipose tissue macrophage inflammation.
Ponatinib modulates the metabolic profile of obese mice by inhibiting adipose tissue macrophage inflammation.
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DOI：
10.3389/fphar.2022.1040999
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发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
肥胖引起的代谢综合征是一个迅速增长的难题，在全球范围内达到流行病的程度。肥胖脂肪组织中的慢性炎症在代谢综合征中起着关键作用，具有炎症细胞浸润和炎症细胞因子分泌等一系列局部和全身效应。脂肪组织巨噬细胞（ATM）作为这一过程的主要调节因子之一，对于肥胖相关代谢综合征的药理学研究尤为重要。帕纳替尼是一种多靶点酪氨酸激酶抑制剂，最初用于治疗白血病，最近发现它可以改善血脂异常和动脉粥样硬化，这表明它可能对代谢综合征产生深远的影响，尽管其潜在机制尚未揭示。在这里，我们发现普纳替尼显着改善了瘦素缺乏的肥胖小鼠的胰岛素敏感性。除此之外，普纳替尼治疗显着改善高脂肪饮食引起的高脂血症并抑制肝脏中的异位脂质沉积。有趣的是，虽然ponatinib没有减少而是增加了白色脂肪组织（WAT）的重量，但它显着抑制了WAT的炎症反应并保留了其功能。从机制上讲，我们发现普纳替尼对肝细胞或脂肪细胞没有直接影响，但减弱的游离脂肪酸（FFA）诱导巨噬细胞从促炎表型转变为抗炎表型。此外，与FFA处理的巨噬细胞共培养的脂肪细胞表现出胰岛素抵抗，而用ponatinib预处理这些巨噬细胞可以改善这一过程。这些结果表明，ponatinib对代谢紊乱的有益作用是通过抑制ATM的炎症表型转化来实现的，从而维持过度肥胖下脂肪组织的生理功能。这里的数据不仅揭示了ponatinib的新颖治疗功能，也为多靶点酪氨酸激酶抑制剂在代谢疾病中的应用提供了理论基础。
Obesity-induced metabolic syndrome is a rapidly growing conundrum, reaching epidemic proportions globally. Chronic inflammation in obese adipose tissue plays a key role in metabolic syndrome with a series of local and systemic effects such as inflammatory cell infiltration and inflammatory cytokine secretion. Adipose tissue macrophages (ATM), as one of the main regulators in this process, are particularly crucial for pharmacological studies on obesity-related metabolic syndrome. Ponatinib, a multi-targeted tyrosine kinase inhibitor originally used to treat leukemia, has recently been found to improve dyslipidemia and atherosclerosis, suggesting that it may have profound effect on metabolic syndrome, although the mechanisms underlying have not yet been revealed. Here we discovered that ponatinib significantly improved insulin sensitivity in leptin deficient obese mice. In addition to that, ponatinib treatment remarkably ameliorated high fat diet-induced hyperlipidemia and inhibited ectopic lipid deposition in the liver. Interestingly, although ponatinib did not reduce but increase the weight of white adipose tissue (WAT), it remarkably suppressed the inflammatory response in WAT and preserved its function. Mechanistically, we showed that ponatinib had no direct effect on hepatocyte or adipocyte but attenuated free fatty acid (FFA) induced macrophage transformation from pro-inflammatory to anti-inflammatory phenotype. Moreover, adipocytes co-cultured with FFA-treated macrophages exhibited insulin resistance, while pre-treat these macrophages with ponatinib can ameliorate this process. These results suggested that the beneficial effects of ponatinib on metabolic disorders are achieved by inhibiting the inflammatory phenotypic transformation of ATMs, thereby maintaining the physiological function of adipose tissue under excessive obesity. The data here not only revealed the novel therapeutic function of ponatinib, but also provided a theoretical basis for the application of multi-target tyrosine kinase inhibitors in metabolic diseases.
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影响因子：
3.7
作者：
Jablonski KA;Amici SA;Webb LM;Ruiz-Rosado Jde D;Popovich PG;Partida-Sanchez S;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
DOI：
10.1124/jpet.112.192187
发表时间：
2012-07-01
影响因子：
3.5
作者：
Ochman, Alexander R.;Lipinski, Christopher A.;Saporito, Michael S.
通讯作者：
Saporito, Michael S.
Ponatinib 通过调节 Wnt 信号和 vasohibin-2/vasohibin-1 减轻实验性肺动脉高压
影响因子：
6.1
作者：
Kang, Zechun;Ji, Yunxia;Jiang, Wanglin
通讯作者：
Jiang, Wanglin
影响因子：
8.2
作者：
McLaughlin T;Deng A;Yee G;Lamendola C;Reaven G;Tsao PS;Cushman SW;Sherman A
通讯作者：
Sherman A
影响因子：
20.3
作者：
Cougoule, Celine;Le Cabec, Veronique;Maridonneau-Parini, Isabelle
通讯作者：
Maridonneau-Parini, Isabelle