Chronic ethanol feeding decreases insulin-stimulated glucose uptake in rat adipocytes. Here we show that chronic ethanol also decreases endothelin-stimulated glucose uptake. Endothelin-1 increased uptake of 2-deoxyglucose by 2.4-fold in adipocytes isolated from pair-fed rats. However, in adipocytes isolated from rats that had consumed a diet containing 35% ethanol for 4 weeks, endothelin-1 did not increase glucose uptake. While endothelin-1 increased GLUT4 quantity at the plasma membrane in adipocytes from pair-fed rats, there was no increase in GLUT4 after chronic ethanol feeding. Loss of endothelin-1 stimulated glucose uptake after ethanol feeding was associated with a specific decrease in the quantity of G₁₁ in plasma membranes, with no change in G_q quantity. Activation of PYK2 (proline-rich tyrosine kinase 2), a down-stream target of G_q/11 which is required for endothelin-1 stimulated GLUT4 translocation in 3T3-L1 adipocytes, was also suppressed after chronic ethanol feeding. In contrast, activation of p38 mitogen activated protein kinase by endothelin-1 was not affected by chronic ethanol exposure. These data demonstrate that chronic ethanol feeding suppreses endothelin-1 stimulated glucose uptake and suggest that decreased expression of G₁₁ coupled to impaired endothelin-1 dependent activation of PYK2 contributes to this response.