Long-term ethanol exposure inhibits glucose transporter 4 expression via an AMPK-dependent pathway in adipocytes.
OBJECTIVE
The roles of AMP-activated protein kinase (AMPK) and myocyte enhancer factor 2 isoforms (MEF2A, 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, MEF2A, 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.


CONCLUSIONS
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.
Feng
Li
L
Provincial Hospital Affiliated to Shandong University, Institute of Endocrinology, Shandong Academy of Clinical Medicine, Ji-nan, China.
Song
Yong-feng
YF
Guan
Qing-bo
QB
Liu
Hong-jun
HJ
Ban
Bo
B
Dong
Hai-xin
HX
Hou
Xiao-lei
XL
Lee
Kok-onn
KO
Gao
Ling
L
Zhao
Jia-jun
JJ
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000209:etiology; D051275:Glucose Transporter Type 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D064326:MEF2 Transcription Factors; D008297:Male; D018006:Myogenic Regulatory Factors / Q000235:genetics; D051381:Rats; D013997:Time Factors
D051275:Glucose Transporter Type 4; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D000431:Ethanol; D055372:AMP-Activated Protein Kinases