Department of Physiology, School of Medicine, Jinan University, Guangzhou, China.
Department of Pathology, School of Basic Medicine, Guangzhou Medical University, Guangzhou, China.
Nat Metab. 2024 Mar;6(3):458-472. doi: 10.1038/s42255-024-00995-z. Epub 2024 Mar 11.
Ghrelin, produced mainly by gastric X/A-like cells, triggers a hunger signal to the central nervous system to stimulate appetite. It remains unclear whether X/A-like cells sense gastric distention and thus regulate ghrelin production. Here we show that PIEZO1 expression in X/A-like cells decreases in patients with obesity when compared to controls, whereas it increases after sleeve gastrectomy. Male and female mice with specific loss of Piezo1 in X/A-like cells exhibit hyperghrelinaemia and hyperphagia and are more susceptible to overweight. These phenotypes are associated with impairment of the gastric CaMKKII/CaMKIV-mTOR signalling pathway. Activation of PIEZO1 by Yoda1 or gastric bead implantation inhibits ghrelin production, decreases energy intake and induces weight loss in mice. Inhibition of ghrelin production by Piezo1 through the CaMKKII/CaMKIV-mTOR pathway can be recapitulated in a ghrelin-producing cell line mHypoE-42. Our study reveals a mechanical regulation of ghrelin production and appetite by PIEZO1 of X/A-like cells, which suggests a promising target for anti-obesity therapy.
胃饥饿素主要由胃 X/A 样细胞产生，向中枢神经系统发出饥饿信号，刺激食欲。目前尚不清楚 X/A 样细胞是否能感知胃扩张，从而调节胃饥饿素的产生。本文显示，与对照组相比，肥胖患者的 X/A 样细胞中 PIEZO1 的表达减少，而袖状胃切除术后则增加。X/A 样细胞特异性缺失 Piezo1 的雄性和雌性小鼠表现出高胃饥饿素血症和多食症，并且更容易超重。这些表型与胃 CaMKKII/CaMKIV-mTOR 信号通路的损伤有关。用 Yoda1 或胃珠植入激活 PIEZO1 可抑制胃饥饿素的产生，减少能量摄入，并诱导小鼠体重减轻。在胃饥饿素产生细胞系 mHypoE-42 中，通过 CaMKKII/CaMKIV-mTOR 通路抑制 Piezo1 对胃饥饿素的产生可被重现。本研究揭示了 X/A 样细胞的 PIEZO1 对胃饥饿素产生和食欲的机械调节，提示其可能成为抗肥胖治疗的一个有前途的靶点。
