A new function of the leptin receptor: mediation of the recovery from lipopolysaccharide-induced hypothermia.
Obese (f/f) Koletsky rats lack the leptin receptor (LR), whereas their lean (F/?) counterparts bear a fully functional LR. By using f/f and F/? rats, we studied whether the LR is involved in lipopolysaccharide (LPS)-induced fever and hypothermia. The body temperature responses to LPS (10 or 100 microg/kg iv) were measured in Koletsky rats exposed to a thermoneutral (28 degrees C) or cool (22 degrees C) environment. Rats of both genotypes responded to LPS with fever at 28 degrees C and with dose-dependent hypothermia at 22 degrees C. The fever responses of the f/f and F/? rats were identical. The hypothermic response of the f/f rats was markedly prolonged compared with that of the F/? rats. The prolonged hypothermic response to LPS in the f/f rats was accompanied by enhanced NF-kappaB signaling in the hypothalamus and an exaggerated rise in the plasma concentration of tumor necrosis factor (TNF)-alpha. The f/f rats did not respond to LPS with an increase in the plasma concentration of corticosterone or adrenocorticotropic hormone, whereas their F/? counterparts did. The hypothermic response to TNF-alpha (80 microg/kg iv) was markedly prolonged in the f/f rats. These data show that the LR is essential for the recovery from LPS hypothermia. LR-dependent mechanisms of the recovery from LPS hypothermia include activation of the anti-inflammatory hypothalamo-pituitary-adrenal axis, inhibition of both the production and hypothermic action of TNF-alpha, and suppression of inflammatory (via NF-kappaB) signaling in the hypothalamus.
Steiner
Alexandre A
AA
Systemic Inflammation Laboratory, Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, USA.
Dogan
M Devrim
MD
Ivanov
Andrei I
AI
Patel
Shreya
S
Rudaya
Alla Y
AY
Jennings
David H
DH
Orchinik
Miles
M
Pace
Thaddeus W W
TW
O'connor
Kevin A
KA
Watkins
Linda R
LR
Romanovsky
Andrej A
AA
D000818:Animals; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis; D004660:Encephalitis / Q000139:chemically induced; D005334:Fever / Q000139:chemically induced; D007035:Hypothermia / Q000097:blood / Q000139:chemically induced* / Q000276:immunology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D009765:Obesity / Q000150:complications; D051381:Rats; D011922:Rats, Mutant Strains; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D054411:Receptors, Leptin
D016207:Cytokines; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D003345:Corticosterone