Skeletal Muscle-Specific Activation of Gq Signaling Maintains Glucose Homeostasis

被引:17
作者
Bone, Derek B. J. [1 ]
Meister, Jaroslawna [1 ]
Knudsen, Jonas R. [2 ]
Dattaroy, Diptadip [1 ]
Cohen, Amanda [1 ]
Lee, Regina [1 ]
Lu, Huiyan [3 ]
Metzger, Daniel [4 ]
Jensen, Thomas E. [2 ]
Wess, Jurgen [1 ]
机构
[1] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA
[2] Univ Copenhagen, Sect Mol Physiol, Dept Nutr Exercise & Sports, Copenhagen, Denmark
[3] NIDDK, Mouse Transgen Core Facil, Bethesda, MD 20892 USA
[4] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire, CNRS UMR 7104, INSERM,U1258, Illkirch Graffenstaden, France
关键词
PROTEIN-COUPLED RECEPTORS; G(Q)-COUPLED RECEPTOR; GLUT4; TRANSLOCATION; OXYTOCIN RECEPTOR; KINASE; CONTRACTION; DEFICIENCY; METABOLISM; MEDIATION; TRANSPORT;
D O I
10.2337/db18-0796
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Skeletal muscle (SKM) insulin resistance plays a central role in the pathogenesis of type 2 diabetes. Because G-protein-coupled receptors (GPCRs) represent excellent drug targets, we hypothesized that activation of specific functional classes of SKM GPCRs might lead to improved glucose homeostasis in type 2 diabetes. At present, little is known about the in vivo metabolic roles of the various distinct GPCR signaling pathways operative in SKM. In this study, we tested the hypothesis that selective activation of SKM G(q) signaling can improve SKM glucose uptake and whole-body glucose homeostasis under physiological and pathophysiological conditions. Studies with transgenic mice expressing a G(q)-linked designer GPCR selectively in SKM cells demonstrated that receptor-mediated activation of SKM G(q) signaling greatly promoted glucose uptake into SKM and significantly improved glucose homeostasis in obese, glucose-intolerant mice. These beneficial metabolic effects required the activity of SKM AMPK. In contrast, obese mutant mice that lacked both G alpha(q) and G alpha(11) selectively in SKM showed severe deficits in glucose homeostasis. Moreover, GPCR-mediated activation of G(q) signaling also stimulated glucose uptake in primary human SKM cells. Taken together, these findings strongly suggest that agents capable of enhancing SKM G(q) signaling may prove useful as novel antidiabetic drugs.
引用
收藏
页码:1341 / 1352
页数:12
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