Improved Glucose Intolerance through a Distinct Mouse Olfactory Receptor 23‐Induced Signaling Pathway Mediating Glucose Uptake in Myotubes and Adipocytes

Abstract

Scope: It is aimed to determine the role of mouse olfactory receptor 23 (MOR23) in regulation of glucose uptake in myotubes and adipocytes and investigate whether administration of a possible MOR23 ligand,-cedrene, attenuates the high fat diet (HFD)-induced glucose intolerance by enhancing the OR-mediated signaling pathway in mice. Methods and Results: MOR23 is genetically inactivated by specific small interfering RNA in C2C12 myotubes and 3T3-L1 adipocytes and stimulated with-cedrene under both basal and insulin-stimulated conditions. In addition, Male C57BL/6N mice are fed a normal diet, HFD, or HFD supplemented with 0.2%-cedrene. In C2C12 myotubes and 3T3-L1 adipocytes, genetic inactivation of MOR23 significantly decrease glucose uptake and MOR23 downstream signaling under both basal and insulin-stimulated conditions. On the other hand,-cedrene-mediated MOR23 stimulation results in increased glucose uptake and upregulation of MOR23 signaling molecules, absent in MOR23-depleted myotubes and adipocytes. Moreover, in mice,-cedrene administration ameliorates HFD-induced glucose intolerance. Activation of MOR23 signaling cascade is also confirmed in basal and insulin stimulated skeletal muscles and adipose tissues of-cedrene-treated mice. Conclusions: These findings suggest that MOR23 is a novel factor for the regulation of glucose uptake and whole-body glucose homeostasis and has therapeutic potential for diabetes treatment.

Dietary Bioactive Ingredients Modulating the cAMP Signaling in Diabetes Treatment

“…In addition, some components (piperonal and filbertone) targeting adipose cAMP signaling that have great potential to maintain glucose homeostasis are also introduced in this part. α-Cedrene, a member of the class of organic compounds known as cedrane and iso-cedrane sesquiterpenoids, stimulates glucose uptake by stimulated the GLUT4 translocation to the cytomembrane in the C2C12 myotubes and 3T3-L1 adipocytes via mouse olfactory receptor 23/cAMP/PKA pathway [89]. Pachymic acid, one of the major chemical components of Poria cocos, stimulates glucose uptake via increasing the expression of GLUT4 and enhancing the redistribution of GLUT4 from intracellular vesicles to the plasma membrane of 3T3-L1 adipocytes.…”

“…This progress is through inhibiting the activity of PDE and increasing the level of intracellular cAMP in L6 myocytes and KK-Ay mice [ 87 , 88 ]. Similarly, α-cedrene, the ligand of mouse olfactory receptor 23, stimulates glucose uptake by stimulating the GLUT4 translocation to the cell membrane in the C2C12 myotubes via mouse olfactory receptor 23/cAMP/PKA signaling pathway [ 89 ]. In vivo, Samad et al reported that [6]-gingerol, a major component of zingiber officinale, improves hyperglycemia by stimulating GLUT4 transporters translocation to cytomembrane in skeletal muscle [ 45 ].…”

Ectopic Odorant Receptor Responding to Flavor Compounds: Versatile Roles in Health and Disease

“…Gain-of-function mutation of Adcy3, a downstream signal-transducing molecule in the canonical olfactory signaling machinery, leads to lower body weights and fat mass in mice fed HFD [ 50 ]. Similarly, we later demonstrated that haploinsufficiency of Adcy3 leads to obesity in the absence of hyperphagia in mice fed either HFD or chow [ 51 ].…”

Mitigation of Insulin Resistance by Natural Products from a New Class of Molecules, Membrane-Active Immunomodulators

“…A sesquiterpene α-cedrene [134] from cedarwood oil significantly increased the translocation of GLUT4 and increased glucose uptake in human hepatocytes in vitro, and improved glucose intolerance induced by a high-fat diet in vivo through the activation of the murine olfactory receptor Olfr16 [135]. A similar effect of α-cedrene in mice with IR was ascribed to the interaction of α-cedrene with the murine olfactory receptor 23 (Mor23) [136]. These reports suggest the possible involvement of odorant receptors in the control of IR.…”