ta Pharmacologica Sinica (2010) 31: 329–340; doi: 10.1038/aps.2010.11

Acta Pharmacologica Sinica (2010) 31: 329–340; doi: 10.1038/aps.2010.11; published online 22 February 2010

Original Article

Long-term ethanol exposure inhibits glucose transporter 4 expression via an AMPK-dependent pathway in adipocytes

Li FENG^{1, 2, #}, Yong-feng SONG^{1, #}, Qing-bo GUAN¹, Hong-jun LIU¹, Bo BAN³, Hai-xin DONG³, Xiao-lei HOU¹, Kok-onn LEE⁴, Ling GAO^{1, *}, Jia-jun ZHAO^1,*

¹Provincial Hospital affiliated to Shandong University; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Ji-nan 250021, China; ²Qianfoshan Hospital of Shandong Province, Ji-nan 250014, China; ³Hospital Affiliated to Ji-ning Medical University ⁴Division of Endocrinology, Department of Medicine, National University of Singapore, Singapore

Aim: The roles of AMP-activated protein kinase (AMPK) and myocyte enhancer factor 2 isoforms (MEF 2A , D) as mediators of the effects of ethanol on glucose transporter 4 (GLUT4) expression are unclear. We studied the effects of ethanol in adipocytes in vivo and in vitro.

Methods: Thirty-six male Wistar rats were divided into three groups and given ethanol in a single daily dose of 0, 0.5, or 5 g /kg for 22 weeks. The expression of AMPK, MEF2 isoforms A and D, and GLUT4 was measured and compared in the three groups. The existence of the AMPK/MEF2/GLUT4 pathway in adipocytes and the effects of ethanol on this pathway were studied in (a) epididymal adipose tissue from six male Wistar rats subcutaneously injected with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR, an AMPK activator) or with 0.9% NaCl (control); and (b) isolated rat and human adipocytes treated with or without ethanol, AICAR, and compound C (a selective AMPK inhibitor). Expression of AMPK, MEF2, and GLUT4 was measured by RT-PCR and Western blotting.

Results: (1) Long-term ethanol exposure decreased activated AMPK, MEF 2A , MEF2D, and GLUT4 expression in rat adipose tissue. (2) In rat and human adipocytes, AICAR-induced AMPK activation, with subsequent elevation of MEF2 and GLUT4 expression, was inhibited by compound C. (3) In vitro ethanol-treatment suppressed the AMPK/MEF2/GLUT4 pathway.

Conclusion: The AMPK/MEF2/GLUT4 pathway exists in both rat and human adipocytes, and activated AMPK may positively regulate MEF2 and GLUT4 expression. Ethanol inhibition of this pathway leads to decreased GLUT4 expression, thus reducing insulin sensitivity and glucose tolerance.

Keywords: ethanol; adipose tissue; AMP-activated protein kinase; myocyte enhancer factor 2; glucose transporter 4

This work was supported by grants from the National Natural Science Foundation of China (No 30940038) and the Natural Science Foundation of Shandong Province, China (No 2009ZRB14271, Y 2001C 12). The authors acknowledge the expert technical assistance by teachers in the central laboratory and experimental animal center of the Provincial Hospital affiliated to Shandong University . The authors thank Prof Harvest F GU for critical review of the manuscript. Partial data from this work were presented at the 67th ADA Annual Meeting (2007-A-2399-Diabetes), 43rd EASD Annual Meeting (A-07-2149-EASD), 44th EASD Annual Meeting (A-08-1890-EASD), and 45th EASD Annual Meeting (A-09-2096-EASD).

^#These authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail jjzhao@medmail.com.cn (Jia-jun ZHAO); gaoling1@medmail.com.cn (Ling GAO).
Received 2009-11-29 Accepted 2010-01-12

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