NF-κB Activation in Hypothalamic Pro-opiomelanocortin Neurons Is Essential in Illness- and Leptin-induced Anorexia

• Published in: The Journal of biological chemistry Vol. 285; no. 13; pp. 9706 - 9715
• Main Authors: Jang, Pil-Geum, Namkoong, Cherl, Kang, Gil Myoung, Hur, Man-Wook, Kim, Seung-Whan, Kim, Geun Hyang, Kang, Yeoungsup, Jeon, Min-Jae, Kim, Eun Hee, Lee, Myung-Shik, Karin, Michael, Baik, Ja-Hyun, Park, Joong-Yeol, Lee, Ki-Up, Kim, Young-Bum, Kim, Min-Seon
• Format: Journal Article
• Language: English
• Published: 9650 Rockville Pike, Bethesda, MD 20814, U.S.A Elsevier Inc 26.03.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Diseases; Diseases/Metabolic; Hormones; Metabolism; Metabolism/Energy; Metabolism/Metabolic Syndrome; Neurobiology; Diseases/Metabolic; Hormones; Metabolism; Metabolism/Energy; Metabolism/Metabolic Syndrome; Diseases
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.070706

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-κB (NF-κB), 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-κB. In vitro, NF-κB 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-κB 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-κB and melanocortin. Furthermore, disruption of IκB kinase-β, an upstream kinase of NF-κB, in POMC neurons attenuated LPS- and Tat-induced anorexia. These findings suggest that infection-associated anorexia and weight loss are mediated via NF-κB activation in hypothalamic POMC neurons. In addition, hypothalamic NF-κB was activated by leptin, an important anorexigenic hormone, and mediates leptin-stimulated POMC transcription, indicating that hypothalamic NF-κB also serves as a downstream signaling pathway of leptin.