Leptin, an adipokine, a major regulator of food intake, was recently suggested to play a role in immune response. We previously showed that weight reduction following IFN alpha therapy is due, at least in part, to direct induction of adipose tissue apoptosis. We now studied the effect of leptin on IFN alpha treated adipocytes in vitro and in vivo. Diet induced obese C57/136 mice were treated continually with recombinant (r) IFM alpha/D + leptin (100 U/g body weight + 10 mu g/day, respectably) or leptin (10 mu g/day) alone for 8 days. Co-administration of IFN alpha A/D + leptin significantly reduced plasma cholesterol (P < 0.001), glucose (P < 0.007) and pro-apoptotic protein levels (P < 0.05). Additionally, co-administration prevented loss of body weight due to adipocyte apoptosis. Thus, leptin co-administration with IFMA/D decreases some of the side effects of IFN alpha administration such as weight loss, cholesterol and glucose levels. (c) 2007 Elsevier Inc. All rights reserved.