In vivo effects of interferon-alpha and interferon-gamma on lipolysis and ketogenesis.

Abstract

The host response to infection and cancer produces disturbances in fatty acid (FA) oxidation and ketogenesis. Interferons (IFNs) stimulatelipolysis in cultured adipocytes. Since FA mobilization is a majorstimulus for ketogenesis, we studied the effect of IFNα and IFNγ onlipolysis and ketogenesis in intact mice. Both IFNs acutely stimulatedlipolysis; however, their effects on ketogenesis differed. INFγ increasedserum and hepatic ketone body levels in parallel to its effect on serumFFA, whereas IFNα exerted a biphasic effect on ketogenesis. At lowdoses, IFNα increased serum and hepatic ketone body levels, whereasat higher doses, this ketogenic effect was abolished. To determine themechanism of the biphasic response, we studied the effect of IFNα onhepatic malonyl-coenzyme-A (malonyl-CoA), the first committed in termediate in FA synthesis and an inhibitor of FA oxidation and ketogenesis. At low doses, IFNα had no effect on malonyl-CoA; however, higher doses of IFNα significantly increased malonyl-CoA levels, which could counterbalance its mobilization of FFA. In contrast, INFγhad little effect on malonyl-CoA, and hence, the FA oxidation was notopposed. By using phenylisopropyladenosine to block IFN-inducedlipolysis, we found that in the absence of increased FA flux, INFγ didnot exert a ketogenic effect. However, when IFNα-induced lipolysiswas blocked, the higher doses of IFNα that raise malonyl-CoA levelswere antiketogenic. These data suggest that both IFNs exert a ketogeniceffect by stimulating lipolysis, but at higher doses the ketogenic effectof IFNα is counteracted by its effect on hepatic FA synthesis. © 1992 by The Endocrine Society.