BACKGROUND Cathepsin L and some other cathepsins have been implicated in the development of obesity in humans and mice. The functional inactivation of the proteases reduces fat accumulation during mammalian adipocyte differentiation. However, beyond degrading extracellular matrix protein fibronectin, the molecular mechanisms by which cathepsins control fat accumulation remain unclear. We now provide evidence from Caenorhabditis elegans and mouse models to suggest a conserved regulatory circuit in which peripheral cathepsin L inhibition lowers fat accumulation through promoting central serotonin synthesis. RESULTS We established a C. elegans model of fat accumulation using dietary supplementation with glucose and palmitic acid. We found that nutrient supplementation elevated fat storage in C. elegans, and along with worm fat accumulation, an increase in the expression of cpl-1 was detected using real-time PCR and western blot. The functional inactivation of cpl-1 reduced fat storage in C. elegans through activating serotonin signaling. Further, knockdown of cpl-1 in the intestine and hypodermis promoted serotonin synthesis in worm ADF neurons and induced body fat loss in C. elegans via central serotonin signaling. We found a similar regulatory circuit in high-fat diet-fed mice. Cathepsin L knockout promoted fat loss and central serotonin synthesis. Intraperitoneal injection of the cathepsin L inhibitor CLIK195 similarly reduced body weight gain and white adipose tissue (WAT) adipogenesis, while elevating brain serotonin level and WAT lipolysis and fatty acid β-oxidation. These effects of inhibiting cathepsin L were abolished by intracranial injection of p-chlorophenylalanine, inhibitor of a rate-limiting enzyme for serotonin synthesis. CONCLUSION This study reveals a previously undescribed molecular mechanism by which peripheral CPL-1/cathepsin L inhibition induces fat loss in C. elegans and mice through promoting central serotonin signaling.

中文翻译：

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外周组织蛋白酶 L 抑制通过促进中枢血清素合成来诱导秀丽隐杆线虫和小鼠的脂肪减少。


背景组织蛋白酶L和一些其他组织蛋白酶与人类和小鼠肥胖的发生有关。蛋白酶的功能失活减少了哺乳动物脂肪细胞分化过程中的脂肪积累。然而，除了降解细胞外基质蛋白纤连蛋白之外，组织蛋白酶控制脂肪积累的分子机制仍不清楚。我们现在提供来自秀丽隐杆线虫和小鼠模型的证据，表明存在一个保守的调节回路，其中外周组织蛋白酶 L 抑制通过促进中枢血清素合成来降低脂肪积累。结果我们通过膳食补充葡萄糖和棕榈酸建立了秀丽隐杆线虫脂肪积累模型。我们发现，营养补充增加了线虫的脂肪储存，并且随着线虫脂肪积累，使用实时 PCR 和蛋白质印迹检测到 cpl-1 表达的增加。 cpl-1 的功能性失活通过激活血清素信号传导减少了秀丽隐杆线虫的脂肪储存。此外，肠道和皮下组织中 cpl-1 的敲低促进了蠕虫 ADF 神经元中血清素的合成，并通过中枢血清素信号传导诱导秀丽隐杆线虫体内脂肪减少。我们在高脂肪饮食喂养的小鼠中发现了类似的调节回路。组织蛋白酶 L 敲除促进脂肪减少和中枢血清素合成。腹腔注射组织蛋白酶 L 抑制剂 CLIK195 同样可以减少体重增加和白色脂肪组织 (WAT) 脂肪生成，同时提高脑血清素水平以及 WAT 脂肪分解和脂肪酸 β-氧化。颅内注射对氯苯丙氨酸（5-羟色胺合成限速酶抑制剂）消除了组织蛋白酶 L 的抑制作用。 结论 这项研究揭示了一种先前未描述的分子机制，即外周 CPL-1/组织蛋白酶 L 抑制通过促进中枢血清素信号传导来诱导秀丽隐杆线虫和小鼠脂肪减少。