Leptin deficiency enhances sensitivity to endotoxin-induced lethality.
Leptin is induced by lipopolysaccharide (LPS) and cytokines. We investigated the role of leptin in LPS-induced toxicity using leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice. Sensitivity to LPS-induced mortality is significantly greater in ob/ob mice compared with their own lean littermates but not in db/db mice. LPS reduced serum glucose in both ob/ob and db/db mice but induced corticosterone only in db/db mice. Despite the very high basal levels of serum leptin in db/db mice, a twofold increase in serum leptin levels was observed after LPS in both db/db mice and their lean littermates. No differences were detected in LPS-induced serum levels of interleukin (IL)-1beta, tumor necrosis factor, macrophage inflammatory protein-1alpha, and interferon-gamma in ob/ob mice compared with their own littermates. In contrast, a blunted induction of IL-10 and IL-1 receptor antagonist (IL-1Ra) was observed in ob/ob mice compared with their littermates. In vitro, leptin induced IL-1Ra production and upregulated the IL-1Ra induction by LPS in macrophages. Moreover, treatment with leptin reversed the increased sensitivity to LPS-induced lethality found in ob/ob mice. These results suggest that leptin participates in the host response to inflammation by modulating the host immune and cytokine responses after LPS.
Faggioni
R
R
Metabolism Section, Department of Veterans Affairs Medical Center, University of California, San Francisco, California 94121, USA.
Fantuzzi
G
G
Gabay
C
C
Moser
A
A
Dinarello
C A
CA
Feingold
K R
KR
Grunfeld
C
C
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000097:blood; D004351:Drug Resistance; D004731:Endotoxins / Q000506:poisoning*; D005260:Female; D020738:Leptin; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis; D054411:Receptors, Leptin
D001786:Blood Glucose; D002352:Carrier Proteins; D016207:Cytokines; D004731:Endotoxins; D020738:Leptin; D008070:Lipopolysaccharides; D011506:Proteins; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D003345:Corticosterone