Leptin deficiency enhances sensitivity to endotoxin-induced lethality

Am J Physiol. 1999 Jan;276(1):R136-42. doi: 10.1152/ajpregu.1999.276.1.R136.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Corticosterone / blood
  • Cytokines / blood
  • Drug Resistance
  • Endotoxins / poisoning*
  • Female
  • Leptin
  • Lipopolysaccharides / pharmacology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL / genetics
  • Obesity / genetics
  • Obesity / metabolism
  • Proteins / metabolism
  • Proteins / pharmacology
  • Proteins / physiology*
  • Receptors, Cell Surface*
  • Receptors, Interleukin-1 / biosynthesis
  • Receptors, Leptin

Substances

  • Blood Glucose
  • Carrier Proteins
  • Cytokines
  • Endotoxins
  • Leptin
  • Lipopolysaccharides
  • Proteins
  • Receptors, Cell Surface
  • Receptors, Interleukin-1
  • Receptors, Leptin
  • leptin receptor, mouse
  • Corticosterone