title: NF-kappaB activation in hypothalamic pro-opiomelanocortin neurons is essential in illness- and leptin-induced anorexia.
abstract: Anorexia and weight loss are prevalent in infectious diseases. To investigate the molecular mechanisms underlying these phenomena, we established animal models of infection-associated anorexia by administrating bacterial and viral products, lipopolysaccharide (LPS) and human immunodeficiency virus-1 transactivator protein (Tat). In these models, we found that the nuclear factor-kappaB (NF-kappaB), a pivotal transcription factor for inflammation-related proteins, was activated in the hypothalamus. In parallel, administration of LPS and Tat increased hypothalamic pro-inflammatory cytokine production, which was abrogated by inhibition of hypothalamic NF-kappaB. In vitro, NF-kappaB activation directly stimulated the transcriptional activity of pro-opiomelanocortin (POMC), a precursor of anorexigenic melanocortin, and mediated the stimulatory effects of LPS, Tat, and pro-inflammatory cytokines on POMC transcription, implying the involvement of NF-kappaB in controlling feeding behavior. Consistently, hypothalamic injection of LPS and Tat caused a significant reduction in food intake and body weight, which was prevented by blockade of NF-kappaB and melanocortin. Furthermore, disruption of I kappaB kinase-beta, an upstream kinase of NF-kappaB, in POMC neurons attenuated LPS- and Tat-induced anorexia. These findings suggest that infection-associated anorexia and weight loss are mediated via NF-kappaB activation in hypothalamic POMC neurons. In addition, hypothalamic NF-kappaB was activated by leptin, an important anorexigenic hormone, and mediates leptin-stimulated POMC transcription, indicating that hypothalamic NF-kappaB also serves as a downstream signaling pathway of leptin.
authors.affiliation: Asan Institute for Life Sciences, Seoul 138-736, Korea.
authors.forename: Pil-Geum
authors.initials: PG
authors.lastname: Jang
authors.affiliation: Asan Institute for Life Sciences, Seoul 138-736, Korea.
authors.forename: Cherl
authors.initials: C
authors.lastname: Namkoong
authors.affiliation: Asan Institute for Life Sciences, Seoul 138-736, Korea.
authors.forename: Gil Myoung
authors.initials: GM
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, Seoul 120-752, Korea.
authors.forename: Man-Wook
authors.initials: MW
authors.lastname: Hur
authors.affiliation: Department of Pharmacology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Seung-Whan
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Geun Hyang
authors.initials: GH
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Sciences, Seoul 138-736, Korea.
authors.forename: Yeoungsup
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Asan Institute for Life Sciences, Seoul 138-736, Korea.
authors.forename: Min-Jae
authors.initials: MJ
authors.lastname: Jeon
authors.affiliation: Department of Internal Medicine, Seoul 138-736, Korea.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Department of Medicine, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
authors.forename: Ja-Hyun
authors.initials: JH
authors.lastname: Baik
authors.affiliation: Department of Internal Medicine, Seoul 138-736, Korea.
authors.forename: Joong-Yeol
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Seoul 138-736, Korea.
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul 138-736, Korea. Electronic address: mskim@amc.seoul.kr.
authors.forename: Min-Seon
authors.initials: MS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000855:Anorexia / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*
chemical_list: D020738:Leptin; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011333:Pro-Opiomelanocortin