INVIVO EFFECTS OF INTERFERON-ALPHA AND INTERFERON-GAMMA ON LIPOLYSIS AND KETOGENESIS

The host response to infection and cancer produces disturbances in fatty acid (FA) oxidation and ketogenesis. Interferons (IFNs) stimulate lipolysis in cultured adipocytes. Since FA mobilization is a major stimulus for ketogenesis, we studied the effect of IFNalpha and IFNgamma on lipolysis and ketogenesis in intact mice. Both IFNs acutely stimulated lipolysis; however, their effects on ketogenesis differed. INFgamma increased serum and hepatic ketone body levels in parallel to its effect on serum FFA, whereas IFNalpha exerted a biphasic effect on ketogenesis. At low doses, IFNalpha increased serum and hepatic ketone body levels, whereas at higher doses, this ketogenic effect was abolished. To determine the mechanism of the biphasic response, we studied the effect of IFNalpha on hepatic malonyl-coenzyme-A (malonyl-CoA), the first committed intermediate in FA synthesis and an inhibitor of FA oxidation and ketogenesis. At low doses, IFNalpha had no effect on malonyl-CoA; however, higher doses of IFNalpha significantly increased malonyl-CoA levels, which could counterbalance its mobilization of FFA. In contrast, INFgamma had little effect on malonyl-CoA, and hence, the FA oxidation was not opposed. By using phenylisopropyladenosine to block IFN-induced lipolysis, we found that in the absence of increased FA flux, INFgamma did not exert a ketogenic effect. However, when IFNalpha-induced lipolysis was blocked, the higher doses of IFNalpha that raise malonyl-CoA levels were antiketogenic. These data suggest that both IFNs exert a ketogenic effect by stimulating lipolysis, but at higher doses the ketogenic effect of IFNalpha is counteracted by its effect on hepatic FA synthesis.