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NF-kappaB activation in hypothalamic pro-opiomelanocortin neurons is essential in illness- and leptin-induced anorexia.

Authors
 Pil-Geum Jang  ;  Cherl Namkoong  ;  Gil Myoung Kang  ;  Man-Wook Hur  ;  Seung-Whan Kim  ;  Geun Hyang Kim  ;  Yeoungsup Kang  ;  Min-Jae Jeon  ;  Eun Hee Kim  ;  Myung-Shik Lee  ;  Michael Karin  ;  Ja-Hyun Baik  ;  Joong-Yeol Park  ;  Ki-Up Lee  ;  Young-Bum Kim  ;  Min-Seon Kim 
Citation
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.285(13) : 9706-9715, 2010 
Journal Title
 JOURNAL OF BIOLOGICAL CHEMISTRY 
ISSN
 0021-9258 
Issue Date
2010
MeSH
Animals ; Anorexia/metabolism* ; Cell Line, Tumor ; Humans ; Hypothalamus/metabolism* ; Leptin/metabolism* ; Lipopolysaccharides/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Microscopy, Fluorescence/methods ; Models, Biological ; NF-kappa B/metabolism* ; Neurons/metabolism* ; Pro-Opiomelanocortin/metabolism*
Keywords
Diseases ; Diseases/Metabolic ; Hormones ; Metabolism ; Metabolism/Energy ; Metabolism/Metabolic Syndrome
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.
Files in This Item:
T201005636.pdf Download
DOI
10.1074/jbc.M109.070706
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Hur, Man Wook(허만욱) ORCID logo https://orcid.org/0000-0002-3416-1334
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/103170
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