CNS leptin action modulates immune response and survival in sepsis.
Sepsis describes a complex clinical syndrome that results from an infection, setting off a cascade of systemic inflammatory responses that can lead to multiple organ failure and death. Leptin is a 16 kDa adipokine that, among its multiple known effects, is involved in regulating immune function. Here we demonstrate that leptin deficiency in ob/ob mice leads to higher mortality and more severe organ damage in a standard model of sepsis in mice [cecal ligation and puncture (CLP)]. Moreover, systemic leptin replacement improved the immune response to CLP. Based on the molecular mechanisms of leptin regulation of energy metabolism and reproductive function, we hypothesized that leptin acts in the CNS to efficiently coordinate peripheral immune defense in sepsis. We now report that leptin signaling in the brain increases survival during sepsis in leptin-deficient as well as in wild-type mice and that endogenous CNS leptin action is required for an adequate systemic immune response. These findings reveal the existence of a relevant neuroendocrine control of systemic immune defense and suggest a possible therapeutic potential for leptin analogs in infectious disease.
Tschöp
Johannes
J
Clinic for Anaesthesiology, Klinikum Grosshadern, Ludwig Maximilians University, D-81375 Munich, Germany.
Nogueiras
Ruben
R
Haas-Lockie
Sarah
S
Kasten
Kevin R
KR
Castañeda
Tamara R
TR
Huber
Nadine
N
Guanciale
Kelsey
K
Perez-Tilve
Diego
D
Habegger
Kirk
K
Ottaway
Nickki
N
Woods
Stephen C
SC
Oldfield
Brian
B
Clarke
Iain
I
Chua
Streamson
S
Farooqi
I Sadaf
IS
O'Rahilly
Stephen
S
Caldwell
Charles C
CC
Tschöp
Matthias H
MH
D000818:Animals; D016470:Bacteremia / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D001921:Brain / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D020738:Leptin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015213:Neuroimmunomodulation / Q000502:physiology; D009504:Neutrophils / Q000378:metabolism; D011897:Random Allocation; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality
D020738:Leptin; D054411:Receptors, Leptin; C515447:leptin receptor, mouse