Acipimox is a nicotinic acid-derived antilipolytic drug devoid of major side effects, and has been used in a number of human trials. This work reports the effects of Acipimox on leptin production from isolated rat adipocytes, in comparison with nicotinic acid and insulin. For cells isolated from normal animals, all these three reagents stimulated leptin release to a similar extent. Acipimox and nicotinic acid were more potent than insulin in stimulating leptin release from cells isolated from diabetic animals, probably because of impaired insulin sensitivity in cells from these diseased animals. Co-incubation of Acipimox with norepinephrine or dibutyryl cAMP diminished its stimulatory effects on leptin release, in parallel with increased lipolysis, suggesting that intracellular free fatty acids play an important role in mediating leptin production in adipocytes.