title: A new function of the leptin receptor: mediation of the recovery from lipopolysaccharide-induced hypothermia.
abstract: 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.
authors.affiliation: Systemic Inflammation Laboratory, Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, USA.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Steiner
authors.forename: M Devrim
authors.initials: MD
authors.lastname: Dogan
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Ivanov
authors.forename: Shreya
authors.initials: S
authors.lastname: Patel
authors.forename: Alla Y
authors.initials: AY
authors.lastname: Rudaya
authors.forename: David H
authors.initials: DH
authors.lastname: Jennings
authors.forename: Miles
authors.initials: M
authors.lastname: Orchinik
authors.forename: Thaddeus W W
authors.initials: TW
authors.lastname: Pace
authors.forename: Kevin A
authors.initials: KA
authors.lastname: O'connor
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.forename: Andrej A
authors.initials: AA
authors.lastname: Romanovsky
mesh_terms: 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
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D003345:Corticosterone