title: Differential effects of interleukin-1 and tumor necrosis factor on ketogenesis.
abstract: To determine the role of cytokines in mediating the decrease in ketones associated with infection, we studied the effect of endotoxin (LPS), interleukin-1 (IL-1), and tumor necrosis factor (TNF) on serum and hepatic ketone body levels (KB), serum free fatty acids (FFA), and hepatic malonyl-CoA levels. LPS decreased serum and hepatic KB in C57Bl/6 (LPS sensitive) mice, whereas it had little effect in C3H/HeJ (LPS resistant) mice, whose macrophages lack the ability to produce IL-1 and TNF in response to LPS, suggesting that IL-1 and TNF may mediate this effect. IL-1 and TNF decreased serum KB in both strains of mice. As seen with LPS, IL-1 decreased hepatic KB, whereas TNF had no such effect. LPS, IL-1, and TNF increased hepatic malonyl-CoA levels. TNF acutely raised serum FFA, whereas LPS and IL-1 did not. Postulating that the TNF-induced increase in FFA overrides the inhibitory effect of malonyl-CoA on fatty acid oxidation and ketogenesis, we used R-2-phenylisopropyladenosine to block TNF-induced lipolysis and demonstrated that in the absence of increased fatty acid flux, TNF inhibits KB formation. As seen with LPS, IL-1, but not TNF, decreased KB in the fasting state. These data suggest that IL-1 and TNF may mediate the antiketogenic effect of infection and that IL-1 has properties closest to that of LPS.
authors.affiliation: Department of Medicine, University of California, San Francisco 94143.
authors.forename: R A
authors.initials: RA
authors.lastname: Memon
authors.forename: K R
authors.initials: KR
authors.lastname: Feingold
authors.forename: A H
authors.initials: AH
authors.lastname: Moser
authors.forename: W
authors.initials: W
authors.lastname: Doerrler
authors.forename: S
authors.initials: S
authors.lastname: Adi
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: C
authors.initials: C
authors.lastname: Grunfeld
mesh_terms: D000818:Animals; D004351:Drug Resistance / Q000235:genetics; D004731:Endotoxins / Q000494:pharmacology; D004926:Escherichia coli; D005230:Fatty Acids, Nonesterified / Q000097:blood; D007375:Interleukin-1 / Q000494:pharmacology*; D007657:Ketone Bodies / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D004731:Endotoxins; D005230:Fatty Acids, Nonesterified; D007375:Interleukin-1; D007657:Ketone Bodies; D014409:Tumor Necrosis Factor-alpha