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

Abstract

Aim: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. 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.

Biphasic effects of chronic ethanol exposure on insulin‐stimulated glucose uptake in primary cultured rat skeletal muscle cells: role of the Akt pathway and GLUT4

“…Compared with lifetime abstainers, alcohol consumption is most protective with respect to the relative risk for type 2 diabetes when consuming 22 g/day alcohol in men and 24 g/day alcohol in women, but becomes detrimental at just over 60 g/day alcohol in men and 50 g/day alcohol in women [1]. The deterioration of insulin signalling by excessive alcohol intake in animal models and the potential underlying mechanisms have been previously reported [10,12,[21][22][23][24]; however, the biphasic effect of alcohol on insulin signalling and the underlying biological mechanisms have not been well proposed [25,26]. The present study demonstrates that chronic ethanol treatment has dose-dependent biphasic effects on insulin-stimulated glucose uptake in primary cultured rat skeletal muscle cells.…”

Alcohol, Adipose Tissue and Lipid Dysregulation

“…A high dose of alcohol (5 g/kg/day) administered via a gastric tube to animals consuming a low fat (10%) chow diet increased eWAT and perirenal depots [22]. On the other hand, lower doses (2.5 and 0.5 g/kg/day) using this same feeding model did not change adipose tissue weight [22,23,24]. Additionally, feeding 5 g/kg/day of alcohol along with a high fat diet (59% fat) prevented the high fat diet induced increase in eWAT mass, suggesting that dietary fat composition has the potential to modulate the alcoholic effect [25].…”

“…Alcohol suppresses ACC Ser79 phosphorylation in vivo [9,18,19,23,25], while in vitro no change and an increase is observed depending on the dose of alcohol [19,25]. This decrease in ACC phosphorylation is consistent with the concomitant reduction in activity of its protein kinase, AMP kinase (AMPK), observed after chronic alcohol consumption [9,18,23,25]. As AMPK activation in adipose tissue can also suppress lipolysis (basal and stimulated), the alcohol-related decrease in AMPK may similarly lead to enhanced lipolysis.…”

Potential Molecular Mechanism of Probiotics in Alcoholic Liver Disease

“…In vivo study, performed with a high dose of alcohol (5 g/kg/day) and low fat (10%) chow diet showed elevated WAT and perirenal lipid depots [68]. Non-significant increase of WAT was seen upon administration of lower dose (2.5 and 0.5 g/kg/day) along with the same feeding pattern [69]. High alcohol dose (5 g/kg/day) along with high-fat diet (59%) delayed WAT mass to increase, indicating that dietary factor plays an important role in modifying alcoholic effect [70].…”