Inhibition of cannabinoid CB1 receptor upregulates Slc2a4 expression via nuclear factor-kappa B and sterol regulatory element-binding protein-1 in adipocytes

Author(s)

Furuya, D. T. ^[1] ; Poletto, A. C. ^[1] ; Freitas, H. S. ^[1] ; Machado, U. F. ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Physiol & Biophys, Inst Biomed Sci, BR-05508900 Sao Paulo - Brazil

• Document type: Journal article
• Source: JOURNAL OF MOLECULAR ENDOCRINOLOGY; v. 49, n. 2, p. 97-106, OCT 2012.
• Web of Science Citations: 15

Abstract

Evidences have suggested that the endocannabinoid system is overactive in obesity, resulting in enhanced endocannabinoid levels in both circulation and visceral adipose tissue. The blockade of cannabinoid receptor type 1 (CB1) has been proposed for the treatment of obesity. Besides loss of body weight, CB1 antagonism improves insulin sensitivity, in which the glucose transporter type 4 (GLUT4) plays a key role. The aim of this study was to investigate the modulation of GLUT4-encoded gene (Slc2a4 gene) expression by CB1 receptor. For this, 3T3-L1 adipocytes were incubated in the presence of a highly selective CB1 receptor agonist (1 mu M arachidonyl-2'-chloroethylamide) and/or a CB1 receptor antagonist/inverse agonist (0.1, 0.5, or 1 mu M AM251, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyra zole-3-carboxamide). After acute (2 and 4 h) and chronic (24 h) treatments, cells were harvested to evaluate: i) Slc2a4, Cnr1 (CB1 receptor-encoded gene), and Srebf1 type a (SREBP-1a type-encoded gene) mRNAs (real-time PCR); ii) GLUT4 protein (western blotting); and iii) binding activity of nuclear factor (NF)-kappa B and sterol regulatory element-binding protein (SREBP)-1 specifically in the promoter of Slc2a4 gene (electrophoretic mobility shift assay). Results revealed that both acute and chronic CB1 receptor antagonism greatly increased (similar to 2.5-fold) Slc2a4 mRNA and protein content. Additionally, CB1-induced upregulation of Slc2a4 was accompanied by decreased binding activity of NF-kappa B at 2 and 24 h, and by increased binding activity of the SREBP-1 at 24 h. In conclusion, these findings reveal that the blockade of CB1 receptor markedly increases Slc2a4/GLUT4 expression in adipocytes, a feature that involves NF-kappa B and SREBP-1 transcriptional regulation. Journal of Molecular Endocrinology (2012) 49, 97-106 (AU)

• FAPESP's process: 07/50554-1 - Glucose transporters and diabetes mellitus: contribution to the knowledge of glycemic control and chronic diseases development
• Grantee: Ubiratan Fabres Machado
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 08/09194-4 - Cannabinoid receptor CB1 modulation of glucose transporter protein GLUT4 in adipocytes 3T3-L1 and visceral adipose tissue of obese mice
• Grantee: Daniela Tomie Furuya
• Support type: Scholarships in Brazil - Post-Doctorate