ANTILIPOLYTIC ACTIONS OF VANADATE AND INSULIN IN RAT ADIPOCYTES MEDIATED BY DISTINCTLY DIFFERENT MECHANISMS

Vanadate, which mimics the biological effects of insulin, also inhibit s Lipolysis in rat adipocytes. Here we demonstrate that the antilipoly tic effect of vanadate differs from that of insulin at least by the fi ve following criteria: 1) vanadate inhibits lipolysis mediated by high (supraphysiological) concentrations of catecholamines; 2) vanadate an tagonizes (Bu)(2)cAMP-mediated lipolysis; 3) vanadate antagonizes isob utylmethylxanthine-dependent lipolysis, 4) vanadate inhibits lipolysis mediated by okadaic acid: and 5) wortmannin, which blocks the antilip olytic effect of insulin. fails to block vanadate-mediated antilipolys is. Vanadate does activate phosphoinositol 3-kinase, and wortmannin bl ocks this activation. Our working hypothesis assumes that all of the i nsulin-hire effects of vanadate, including antilipolysis, are initiate d by the inhibition of protein phosphotyrosine phosphatases (PTPases). Among documented PTPase inhibitors we found that VOSO4 (oxidation sta te +4), several organic vanadyl compounds (+4), zinc (Zn2+), tungstate (W), and molybdate (Mo) also had antilipolytic activity. The order of potency was vanadyl acetylacetonate greater than or equal to VOSO4 gr eater than or equal to NaVO3 greater than or equal to vanadyldipicolin ate > Zn2+ W > Mo, and ii; correlated better with the inhibition of ad ipose membranal-PTPases in cell-free? experiments. We have concluded t hat the antilipolytic effect of vanadate is 1) mechanistically distinc t from that of insulin, 2) independent of phosphoinositol 3-kinase act ivation, and 3) independent of the lipolytic cascade. We also strongly suggest that the antilipolytic effect of vanadate emanates from inhib iting adipose membranal, rather than cytosolic PTPases, and present pr eliminary data showing distinct differences in catalysis between these two PTPase categories. Overall, the study indicates that antilipolysi s can be manifested via alternative, insulin-independent, signal-trans ducing pathways.