利莫那班
敌手
内科学
腺苷酸环化酶
内分泌学
基因敲除
生物
药理学
大麻素受体
受体
细胞生物学
生物化学
医学
刺激
细胞凋亡
作者
Ziyi Liu,Malliga R. Iyer,Grzegorz Godlewski,Tony Jourdan,Jie Liu,Nathan J. Coffey,Charles N. Zawatsky,Henry L. Puhl,Jürgen Wess,Jaroslawna Meister,Jeih‐San Liow,Robert B. Innis,Sergio A. Hassan,Yong Sok Lee,George Kunos,Reşat Çınar
出处
期刊:ACS pharmacology & translational science
[American Chemical Society]
日期:2021-04-08
卷期号:4 (3): 1175-1187
被引量:32
标识
DOI:10.1021/acsptsci.1c00048
摘要
Seven-transmembrane receptors signal via G-protein- and β-arrestin-dependent pathways. We describe a peripheral CB1R antagonist (MRI-1891) highly biased toward inhibiting CB1R-induced β-arrestin-2 (βArr2) recruitment over G-protein activation. In obese wild-type and βArr2-knockout (KO) mice, MRI-1891 treatment reduces food intake and body weight without eliciting anxiety even at a high dose causing partial brain CB1R occupancy. By contrast, the unbiased global CB1R antagonist rimonabant elicits anxiety in both strains, indicating no βArr2 involvement. Interestingly, obesity-induced muscle insulin resistance is improved by MRI-1891 in wild-type but not in βArr2-KO mice. In C2C12 myoblasts, CB1R activation suppresses insulin-induced akt-2 phosphorylation, preventable by MRI-1891, βArr2 knockdown or overexpression of CB1R-interacting protein. MRI-1891, but not rimonabant, interacts with nonpolar residues on the N-terminal loop, including F108, and on transmembrane helix-1, including S123, a combination that facilitates βArr2 bias. Thus, CB1R promotes muscle insulin resistance via βArr2 signaling, selectively mitigated by a biased CB1R antagonist at reduced risk of central nervous system (CNS) side effects.
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