Otsuka Ayano, Jinguji Ayana, Maejima Yuko, Kasahara Yoshiyuki, Shimomura Kenju, Hidema Shizu, Nishimori Katsuhiko
a Department of Molecular and Cell Biology, Graduate School of Agricultural Science , Tohoku University , Sendai , Japan.
b Department of Bioregulation and Pharmacological Medicine, School of Medicine , Fukushima Medical University , Fukushima , Japan.
Biosci Biotechnol Biochem. 2019 Jul;83(7):1336-1342. doi: 10.1080/09168451.2019.1591266. Epub 2019 Mar 27.
Leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4) suppresses food intake after its activation by binding of its ligands, R-spondins. We investigated the mechanism of food intake suppression by R-spondin1 in a region-specific gene knockout (LGR4 cKO) mouse model, generated by deletion of the gene in arcuate nucleus (ARC) using mice combined with infection of an AAV-Cre vector. After R-spondin1 administration, LGR4 cKO mice didn't exhibit a suppressed appetite, compared to that in control mice, which received a vehicle. In ARC of LGR4 cKO mice, mRNA expression was reduced, leading to suppressed food intake. On the other hand, neurons-specific LGR4 KO mice exhibited no differences in expression, and no structural differences were observed in the ARC of mutant mice. These results suggest that LGR4 is an essential part of the mechanism, inducing gene expression with R-spondin1 in ARC neurons in mice, thereby regulating feeding behavior. LGR4: Leucine-rich repeat-containing G-protein coupled receptor 4; RSPOs: roof plate-specific spondins; ARC: arcuate nucleus; AAV: adeno associated virus; POMC: pro-opiomelanocortin; CART: cocaine and amphetamine-regulated transcript; NPY: neuropeptide Y; AgRP: agouti-related peptide; Axin2: axis inhibition protein 2; Lef1: lymphoid enhancer binding factor 1; ccnd1: cyclin D1.
富含亮氨酸重复序列的G蛋白偶联受体4（LGR4）在被其配体R-spondins结合激活后可抑制食物摄入。我们在一个区域特异性基因敲除（LGR4 cKO）小鼠模型中研究了R-spondin1抑制食物摄入的机制，该模型是通过将携带AAV-Cre载体的小鼠与基因敲除小鼠结合，在弓状核（ARC）中删除该基因而产生的。给予R-spondin1后，与接受载体的对照小鼠相比，LGR4 cKO小鼠没有表现出食欲抑制。在LGR4 cKO小鼠的ARC中， mRNA表达降低，导致食物摄入受到抑制。另一方面，神经元特异性LGR4敲除小鼠在 表达上没有差异，在突变小鼠的ARC中也未观察到结构差异。这些结果表明，LGR4是该机制的重要组成部分，在小鼠ARC神经元中与R-spondin1一起诱导 基因表达，从而调节摄食行为。LGR4：富含亮氨酸重复序列的G蛋白偶联受体4；RSPOs：顶板特异性spondins；ARC：弓状核；AAV：腺相关病毒；POMC：阿片促黑皮质素原；CART：可卡因和苯丙胺调节转录物；NPY：神经肽Y；AgRP：刺鼠相关肽；Axin2：轴抑制蛋白2；Lef1：淋巴增强因子1；ccnd1：细胞周期蛋白D1。
