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Ponatinib modulates the metabolic profile of obese mice by inhibiting adipose tissue macrophage inflammation

Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Lin, Zhuomiao;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Lin, Xiaochun;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Lai, Ying;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Han, Congcong;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Fan, Xinran;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Tang, Jie;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Mo, Shiqi;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Su, Jiahui;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Liang, Sijia;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Shang, Jinyan;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Lv, Xiaofei;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Guo, Siwan;
Affiliation
Department of Physiology ,Pain Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Pang, Ruiping;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Zhou, Jiaguo;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Zhang, Tingting;
Affiliation
Department of Pharmacology ,Cardiac and Cerebral Vascular Research Center ,Zhongshan School of Medicine ,Sun Yat-Sen University ,Guangzhou ,China
Zhang, Feiran

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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License Holder: Copyright © 2022 Lin, Lin, Lai, Han, Fan, Tang, Mo, Su, Liang, Shang, Lv, Guo, Pang, Zhou, Zhang and Zhang.

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