Peripheral cathepsin L inhibition induces fat loss in C. elegans and mice through promoting central serotonin synthesis
Peripheral cathepsin L inhibition induces fat loss in C. elegans and mice through promoting central serotonin synthesis
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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诱导秀丽隐杆线虫和小鼠脂肪减少
DOI：
10.1186/s12915-019-0719-4
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发表时间：
2019-11
期刊：
影响因子：
5.4
通讯作者：
Liu Jian
中科院分区：
文献类型：
--
作者：
Lin Yan;Bao Bin;Yin Hao;Wang Xin;Feng Airong;Zhao Lin;Nie Xianqi;Yang Nan;Shi Guo-Ping;Liu Jian
组织蛋白酶L和其他一些组织蛋白酶与人类和小鼠肥胖的发展有关。蛋白酶的功能失活可减少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维连接蛋白外，组织蛋白酶控制脂肪积累的分子机制尚不清楚。我们现在提供了秀丽隐杆线虫和小鼠模型的证据，表明外周组织蛋白酶L抑制通过促进中枢血清素合成来降低脂肪积累的保守调节回路。结果通过在饲料中添加葡萄糖和棕榈酸，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，并且通过实时PCR和western blot检测到随着脂肪积累，cpl-1的表达增加。cpl-1的功能失活通过激活血清素信号来减少脂肪储存。此外，在肠道和皮下敲低ccp -1可促进线虫ADF神经元中5 -羟色胺的合成，并通过中枢5 -羟色胺信号传导诱导体脂减少。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和WAT脂肪分解和脂肪酸β-氧化。这些抑制组织蛋白酶L的作用被颅内注射对氯苯丙氨酸（5 -羟色胺合成限速酶的抑制剂）所消除。结论本研究揭示了外周CPL-1/cathepsin L抑制通过促进中枢5 -羟色胺信号传导诱导秀丽隐杆线虫和小鼠减脂的分子机制。
BackgroundCathepsin 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 fromCaenorhabditis elegansand mouse models to suggest a conserved regulatory circuit in which peripheral cathepsin L inhibition lowers fat accumulation through promoting central serotonin synthesis.ResultsWe established aC. elegansmodel of fat accumulation using dietary supplementation with glucose and palmitic acid. We found that nutrient supplementation elevated fat storage inC. elegans, and along with worm fat accumulation, an increase in the expression ofcpl-1was detected using real-time PCR and western blot. The functional inactivation ofcpl-1reduced fat storage inC. elegansthrough activating serotonin signaling. Further, knockdown ofcpl-1in the intestine and hypodermis promoted serotonin synthesis in worm ADF neurons and induced body fat loss inC. elegansvia 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.ConclusionThis study reveals a previously undescribed molecular mechanism by which peripheral CPL-1/cathepsin L inhibition induces fat loss inC. elegansand mice through promoting central serotonin signaling.
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炎症和代谢疾病中的脂肪因子。
DOI：
10.1038/nri2921
发表时间：
2011-02
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
29
作者：
Noble T;Stieglitz J;Srinivasan S
通讯作者：
Srinivasan S
影响因子：
--
作者：
Zhang SO;Trimble R;Guo F;Mak HY
通讯作者：
Mak HY
影响因子：
3.3
作者：
S. Brenner
通讯作者：
S. Brenner
影响因子：
18.2
作者：
Srinivasan S
通讯作者：
Srinivasan S