Rubiscolin-6 Activates Opioid Receptors to Enhance Glucose Uptake in Skeletal Muscle

Overview

Journal J Food Drug Anal

Specialties Nutritional Sciences
Pharmacology
Toxicology

Date 2019 Jan 17

PMID 30648580

Citations 7

Authors

Timothy Sean Kairupan

Kai-Chun Cheng

Akihiro Asakawa

Haruka Amitani

Takakazu Yagi

Koji Ataka

Natasya Trivena Rokot

Nova Hellen Kapantow

Ikuo Kato

Akio Inui

Affiliations

Soon will be listed here.

Abstract

Rubiscolin-6 is an opioid peptide derived from plant ribulose bisphosphate carboxylase/oxygenase (Rubisco). It has been demonstrated that opioid receptors could control glucose homeostasis in skeletal muscle independent of insulin action. Therefore, Rubiscolin-6 may be involved in the control of glucose metabolism. In the present study, we investigated the effect of rubiscolin-6 on glucose uptake in skeletal muscle. Rubiscolin-6-induced glucose uptake was measured using the fluorescent indicator 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose (2-NBDG) in L6 and C2C12 cell lines. The protein expressions of glucose transporter 4 (GLUT4) and AMP-activated protein kinase (AMPK) in L6 cells were observed by Western blotting. The in vivo effects of rubiscolin-6 were characterized in streptozotocin (STZ)-induced diabetic rats. Rubiscolin-6 induced a concentration-dependent increase in glucose uptake levels. The increase of phospho-AMPK (pAMPK) and GLUT4 expressions were also observed in L6 and C2C12 cells. Effects of rubiscolin-6 were blocked by opioid receptor antagonists and/or associated signals inhibitors. Moreover, Rubiscolin-6 produced a dose-dependent reduction of blood glucose and increased GLUT4 expression in STZ-induced diabetic rats. In conclusion, rubiscolin-6 increases glucose uptake, potentially via an activation of AMPK to enhance GLUT4 translocation after binding to opioid receptors in skeletal muscle.

Citing Articles

Neuroprotective and Anti-inflammatory Effects of Rubiscolin-6 Analogs with Proline Surrogates in Position 2.

Perlikowska R, Silva J, Alves C, Susano P, Zaklos-Szyda M, Skibska A Neurochem Res. 2023; 49(4):895-918.

PMID: 38117448 PMC: 10901950. DOI: 10.1007/s11064-023-04070-z.

Therapeutic Potential of Orally Administered Rubiscolin-6.

Karasawa Y, Miyano K, Yamaguchi M, Nonaka M, Yamaguchi K, Iseki M Int J Mol Sci. 2023; 24(12).

PMID: 37373107 PMC: 10298254. DOI: 10.3390/ijms24129959.

Food-inspired peptides from spinach Rubisco endowed with antioxidant, antinociceptive and anti-inflammatory properties.

Marinaccio L, Zengin G, Pieretti S, Minosi P, Szucs E, Benyhe S Food Chem X. 2023; 18:100640.

PMID: 37008720 PMC: 10064441. DOI: 10.1016/j.fochx.2023.100640.

Rubiscolin‑6 rapidly suppresses the postprandial motility of the gastric antrum and subsequently increases food intake via δ‑opioid receptors in mice.

Ataka K, Asakawa A, Kato I Mol Med Rep. 2022; 26(5).

PMID: 36111502 PMC: 9494588. DOI: 10.3892/mmr.2022.12856.

Pepsin-digested chicken-liver hydrolysate attenuates hepatosteatosis by relieving hepatic and peripheral insulin resistance in long-term high-fat dietary habit.

Wu Y, Lin Y, Yang W, Wang S, Chen Y J Food Drug Anal. 2022; 29(2):375-388.

PMID: 35696203 PMC: 9261818. DOI: 10.38212/2224-6614.3351.

References

Furman B . Streptozotocin-Induced Diabetic Models in Mice and Rats. Curr Protoc Pharmacol. 2015; 70:5.47.1-5.47.20. DOI: 10.1002/0471141755.ph0547s70. View

Nummenmaa L, Tuominen L . Opioid system and human emotions. Br J Pharmacol. 2017; 175(14):2737-2749. PMC: 6016642. DOI: 10.1111/bph.13812. View

Kaneko K, Lazarus M, Miyamoto C, Oishi Y, Nagata N, Yang S . Orally administered rubiscolin-6, a δ opioid peptide derived from Rubisco, stimulates food intake via leptomeningeal lipocallin-type prostaglandin D synthase in mice. Mol Nutr Food Res. 2012; 56(8):1315-23. DOI: 10.1002/mnfr.201200155. View

Lin S, Grahame Hardie D . AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metab. 2017; 27(2):299-313. DOI: 10.1016/j.cmet.2017.10.009. View

Evans A, Tunnicliffe G, Knights P, Bailey C, Smith M . Delta opioid receptors mediate glucose uptake in skeletal muscles of lean and obese-diabetic (ob/ob) mice. Metabolism. 2001; 50(12):1402-8. DOI: 10.1053/meta.2001.28158. View

Jordan B, Devi L . G-protein-coupled receptor heterodimerization modulates receptor function. Nature. 1999; 399(6737):697-700. PMC: 3125690. DOI: 10.1038/21441. View

Cheng J, Liu I, CHI T, Tzeng T, Lu F, Chang C . Plasma glucose-lowering effect of tramadol in streptozotocin-induced diabetic rats. Diabetes. 2001; 50(12):2815-21. DOI: 10.2337/diabetes.50.12.2815. View

Charles A, Mostovskaya N, Asas K, Evans C, Dankovich M, Hales T . Coexpression of delta-opioid receptors with micro receptors in GH3 cells changes the functional response to micro agonists from inhibitory to excitatory. Mol Pharmacol. 2002; 63(1):89-95. DOI: 10.1124/mol.63.1.89. View

Hilder T, Baer L, Fuller P, Fuller C, Grindeland R, Wade C . Insulin-independent pathways mediating glucose uptake in hindlimb-suspended skeletal muscle. J Appl Physiol (1985). 2005; 99(6):2181-8. DOI: 10.1152/japplphysiol.00743.2005. View

10.

Yang T, Liu I, Wu H, Cheng J . Mediation of protein kinase C zeta in mu-opioid receptor activation for increase of glucose uptake into cultured myoblast C2C12 cells. Neurosci Lett. 2009; 465(2):177-80. DOI: 10.1016/j.neulet.2009.08.026. View

11.

Ong E, Cahill C . Molecular Perspectives for mu/delta Opioid Receptor Heteromers as Distinct, Functional Receptors. Cells. 2014; 3(1):152-79. PMC: 3980742. DOI: 10.3390/cells3010152. View

12.

Navale A, Paranjape A . Glucose transporters: physiological and pathological roles. Biophys Rev. 2017; 8(1):5-9. PMC: 5425736. DOI: 10.1007/s12551-015-0186-2. View

13.

Runtuwene J, Cheng K, Asakawa A, Amitani H, Amitani M, Morinaga A . Rosmarinic acid ameliorates hyperglycemia and insulin sensitivity in diabetic rats, potentially by modulating the expression of PEPCK and GLUT4. Drug Des Devel Ther. 2016; 10:2193-202. PMC: 4940010. DOI: 10.2147/DDDT.S108539. View

14.

Caballero J, Saavedra M, Fernandez M, Gonzalez-Nilo F . Quantitative structure-activity relationship of rubiscolin analogues as delta opioid peptides using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). J Agric Food Chem. 2007; 55(20):8101-4. DOI: 10.1021/jf071031h. View

15.

Smart D, Smith G, Lambert D . mu-Opioid receptor stimulation of inositol (1,4,5)trisphosphate formation via a pertussis toxin-sensitive G protein. J Neurochem. 1994; 62(3):1009-14. DOI: 10.1046/j.1471-4159.1994.62031009.x. View

16.

Yang S, Kawamura Y, Yoshikawa M . Effect of rubiscolin, a delta opioid peptide derived from Rubisco, on memory consolidation. Peptides. 2003; 24(2):325-8. DOI: 10.1016/s0196-9781(03)00044-5. View

17.

Towler M, Grahame Hardie D . AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007; 100(3):328-41. DOI: 10.1161/01.RES.0000256090.42690.05. View

18.

Kim J, Park Y . Anti-diabetic effect of sorghum extract on hepatic gluconeogenesis of streptozotocin-induced diabetic rats. Nutr Metab (Lond). 2012; 9(1):106. PMC: 3545981. DOI: 10.1186/1743-7075-9-106. View

19.

Gomes I, Jordan B, Gupta A, Trapaidze N, Nagy V, Devi L . Heterodimerization of mu and delta opioid receptors: A role in opiate synergy. J Neurosci. 2000; 20(22):RC110. PMC: 3125672. View

20.

Radosevich P, Williams P, Lacy D, McRae J, Steiner K, Cherrington A . Effects of morphine on glucose homeostasis in the conscious dog. J Clin Invest. 1984; 74(4):1473-80. PMC: 425317. DOI: 10.1172/JCI111560. View