Inhibition of Plasminogen Activator Inhibitor-1 Activation Suppresses High Fat Diet-Induced Weight Gain via Alleviation of Hypothalamic Leptin Resistance
Inhibition of Plasminogen Activator Inhibitor-1 Activation Suppresses High Fat Diet-Induced Weight Gain via Alleviation of Hypothalamic Leptin Resistance
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DOI：
10.3389/fphar.2020.00943
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发表时间：
2020-06-24
影响因子：
5.6
通讯作者：
Katagiri, Hideki
中科院分区：
文献类型：
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作者：
Hosaka, Shinichiro;Yamada, Tetsuya;Katagiri, Hideki
瘦素抵抗是肥胖发生和维持的重要机制，因此被认为是肥胖治疗的有希望的靶点。纤溶酶原激活物抑制剂1（派-1）是组织型和尿激酶型纤溶酶原激活物的生理抑制剂，在脂肪组织中以高水平产生，特别是在肥胖状态下，并且被认为主要参与血栓形成。派-1还可能在器官间组织通讯中调节体重，因为据报道派-1敲除小鼠表现出对高脂饮食（HFD）诱导的肥胖的抗性。然而，派-1在体重调节中的作用及其机制尚未完全阐明。我们在此研究派-1如何影响全身能量代谢。我们检查了派-1基因敲除小鼠的体重和食物摄入量，这些小鼠喂食正常食物或HFD。我们还研究了小分子量化合物TM 5441对派-1活性的药理学抑制对HFD喂养的野生型（WT）小鼠的体重、瘦素敏感性和棕色脂肪组织（BAT）中产热相关基因表达的影响。在食物喂养条件下，派-1 KO小鼠的体重增加和食物摄入均未减少。另一方面，在HFD喂养条件下，与WT小鼠相比，派-1 KO小鼠的摄食量减少（HFD-WT小鼠3.98 +/- 0.08 g/天vsHFD-KO小鼠3.73 +/- 0.07 g/天，P= 0.021），最终导致体重增加的显著抑制（HFD-WT小鼠40.3 +/-1. 68 gvsHFD-KO小鼠34.6 +/-1.84g，P= 0.039）。此外，预先喂食HFD的WT小鼠的TM 5441处理导致以派-1依赖性方式显著抑制体重增加（HFD-WT-对照小鼠37.6 +/- 1.07 g vsHFD-WT-TM 5441小鼠33.8 +/- 0.97 g，P= 0.017）。TM 5441治疗减轻HFD诱导的全身和下丘脑瘦素抵抗，然后体重增加的抑制是明显的。此外，TM 5441治疗后瘦素敏感性的提高伴随着BAT中产热相关基因如解偶联蛋白1的表达增加（HFD-WT-Control小鼠1.00 +/- 0. 07 vsHFD-WT-TM 5441小鼠1.32 +/-0.05，P = 0.002）。这些结果表明，派-1通过诱导下丘脑瘦素抵抗在HFD喂养条件下的体重增加中起致病作用。此外，他们指出，派-1活性的药理学抑制是减轻肥胖受试者中饮食诱导的瘦素抵抗的潜在策略。
Leptin resistance is an important mechanism underlying the development and maintenance of obesity and is thus regarded as a promising target of obesity treatment. Plasminogen activator inhibitor 1 (PAI-1), a physiological inhibitor of tissue-type and urokinase-type plasminogen activators, is produced at high levels in adipose tissue, especially in states of obesity, and is considered to primarily be involved in thrombosis. PAI-1 may also have roles in inter-organ tissue communications regulating body weight, because PAI-1 knockout mice reportedly exhibit resistance to high fat diet (HFD)-induced obesity. However, the role of PAI-1 in body weight regulation and the underlying mechanisms have not been fully elucidated. We herein studied how PAI-1 affects systemic energy metabolism. We examined body weight and food intake of PAI-1 knockout mice fed normal chow or HFD. We also examined the effects of pharmacological inhibition of PAI-1 activity by a small molecular weight compound, TM5441, on body weight, leptin sensitivities, and expressions of thermogenesis-related genes in brown adipose tissue (BAT) of HFD-fed wild type (WT) mice. Neither body weight gain nor food intake was reduced in PAI-1 KO mice under chow fed conditions. On the other hand, under HFD feeding conditions, food intake was decreased in PAI-1 KO as compared with WT mice (HFD-WT mice 3.98 +/- 0.08 g/dayvsHFD-KO mice 3.73 +/- 0.07 g/day,P= 0.021), leading to an eventual significant suppression of weight gain (HFD-WT mice 40.3 +/- 1.68 gvsHFD-KO mice 34.6 +/- 1.84 g,P= 0.039). Additionally, TM5441 treatment of WT mice pre-fed the HFD resulted in a marked suppression of body weight gain in a PAI-1-dependent manner (HFD-WT-Control mice 37.6 +/- 1.07 gvsHFD-WT-TM5441 mice 33.8 +/- 0.97 g,P= 0.017). TM5441 treatment alleviated HFD-induced systemic and hypothalamic leptin resistance, before suppression of weight gain was evident. Moreover, improved leptin sensitivity in response to TM5441 treatment was accompanied by increased expressions of thermogenesis-related genes such asuncoupling protein 1in BAT (HFD-WT-Control mice 1.00 +/- 0.07vsHFD-WT-TM5441 mice 1.32 +/- 0.05,P= 0.002). These results suggest that PAI-1 plays a causative role in body weight gain under HFD-fed conditions by inducing hypothalamic leptin resistance. Furthermore, they indicate that pharmacological inhibition of PAI-1 activity is a potential strategy for alleviating diet-induced leptin resistance in obese subjects.