The effect of a variety of cytokines on lipid metabolism in 3T3 Li mouse fibroblasts and adipocytes was studied. Uptake of [3H]acetate by adipocytes and heparinreleasable lipoprotein lipase activity was inhibited after treatments of the cells with picomolar concentrations of recombinant human tumor necrosis factor a (rHuTNF-a), human tumor necrosis factor 13 (rHuTNF-f, also called lymphotoxin), murine interferon-y (rMuIFN-y), and a human hybrid interferon-a [rHuIFN-a2/aj (Bgl I)]. Recombinant human interferon-y (rHuIFN-y), natural human colony-stimulating factor (HuCSF), and human interleukin 2 (HuIL-2) had no effect. Similar though less-marked suppression of [3H~acetate uptake by cytokines was seen in 3T3 Li fibroblasts. Cytokines inhibited the incorporation of [3H]acetate into both membrane and storage lipids in the adipocytes. In addition to blocking lipid uptake and synthesis, rHuTNF-a and -(3, and rMuIFN-y stimulated the release of free fatty acid into the medium from adipocytes. Binding studies suggest that rHuTNF-a and rHuTNF-P compete for the same cell-surface receptor on 3T3 Li adipocytes, while rMuIFN-y binds to a separate receptor.The binding of rTNF-a to both adipocytes and fibroblasts can be significantly enhanced by preexposure of the cells to rMuIFN-y. There appear to be both high-and low-affinity receptors for rHuTNF-a on adipocytes, whereas fibroblasts exhibit a single class of high-affinity receptors. These results suggest that a variety of structurally distinct cytokines possess lipid mobilization activity, which may be of critical importance to the host in defense against infection or malignancy.The invasion of the body by viruses, bacteria, or parasites usually elicits an integrated host response that kills and removes the infectious agents and provides immunity against future challenges. Much of the host response is modulated by a class of inducible proteins called cytokines (1-3). It is now clear that there are many distinct host cytokines that can be produced by a wide variety of cell types, including epithelial cells, fibroblasts, tumor cells, and particularly lymphocytes (lymphokines) and macrophages (monokines) (4-6). Tumor necrosis factors (TNFs), interleukins (ILs), and a-, ,B, and -interferons (IFN-a, -(3, and -y) are representative and well-characterized cytokines. Although there is considerable structural and functional heterogeneity among these families of cytokines, they all appear to have roles in the regulation of host immunity and inflammation (7-12). When administered parenterally at high doses they can be toxic, and many of the symptoms associated with the common cold and influenza such as fever, nausea, and muscle aches can be induced by the administration of pure cytokines (13,14). Unraveling the sequence of cytokine actions that occur during the host response to infection is very complex because (i) cytokines regulate the production of one another (15-17), (ii) an individual cell may produce many different cytokines (18, 19), and (iii) different cytokines may hav...