NF-kappaB activation in hypothalamic pro-opiomelanocortin neurons is essential in illness- and leptin-induced anorexia.
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.
Jang
Pil-Geum
PG
Asan Institute for Life Sciences, Seoul 138-736, Korea.
Namkoong
Cherl
C
Asan Institute for Life Sciences, Seoul 138-736, Korea.
Kang
Gil Myoung
GM
Asan Institute for Life Sciences, Seoul 138-736, Korea.
Hur
Man-Wook
MW
Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, Seoul 120-752, Korea.
Kim
Seung-Whan
SW
Department of Pharmacology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
Kim
Geun Hyang
GH
Department of Pharmacology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
Kang
Yeoungsup
Y
Asan Institute for Life Sciences, Seoul 138-736, Korea.
Jeon
Min-Jae
MJ
Asan Institute for Life Sciences, Seoul 138-736, Korea.
Kim
Eun Hee
EH
Department of Internal Medicine, Seoul 138-736, Korea.
Lee
Myung-Shik
MS
Department of Medicine, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
Karin
Michael
M
Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California 92093.
Baik
Ja-Hyun
JH
School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
Park
Joong-Yeol
JY
Department of Internal Medicine, Seoul 138-736, Korea.
Lee
Ki-Up
KU
Department of Internal Medicine, Seoul 138-736, Korea.
Kim
Young-Bum
YB
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215.
Kim
Min-Seon
MS
Department of Internal Medicine, Seoul 138-736, Korea. Electronic address: mskim@amc.seoul.kr.
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*
D020738:Leptin; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011333:Pro-Opiomelanocortin