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

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

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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-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 proopiomelanocortin (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 POMCneurons. 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.

Original languageEnglish
Pages (from-to)9706-9715
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number13
DOIs
Publication statusPublished - 2010 Mar 26

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Pro-Opiomelanocortin
Anorexia
Leptin
Trans-Activators
Neurons
Chemical activation
Lipopolysaccharides
Melanocortins
Proteins
Transcription
Weight Loss
Phosphotransferases
Cytokines
Feeding Behavior
Infection
Viruses
Hypothalamus
Communicable Diseases
HIV-1
Animals

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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

In: Journal of Biological Chemistry, Vol. 285, No. 13, 26.03.2010, p. 9706-9715.

Research output: Contribution to journalArticle

Jang, PG, Namkoong, C, Kang, GM, Hur, MW, Kim, SW, Kim, GH, Kang, Y, Jeon, MJ, Kim, EH, Lee, MS, Karin, M, Baik, J-H, Park, JY, Lee, KU, Kim, YB & Kim, MS 2010, 'NF-κB activation in hypothalamic pro-opiomelanocortin neurons is essential in illness- and leptin-induced anorexia', Journal of Biological Chemistry, vol. 285, no. 13, pp. 9706-9715. https://doi.org/10.1074/jbc.M109.070706
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. / NF-κB activation in hypothalamic pro-opiomelanocortin neurons is essential in illness- and leptin-induced anorexia. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 13. pp. 9706-9715.
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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-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 proopiomelanocortin (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 POMCneurons. 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.",
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T1 - NF-κB activation in hypothalamic pro-opiomelanocortin neurons is essential in illness- and leptin-induced anorexia

AU - Jang, Pil Geum

AU - Namkoong, Cherl

AU - Kang, Gil Myoung

AU - Hur, Man Wook

AU - Kim, Seung Whan

AU - Kim, Geun Hyang

AU - Kang, Yeoungsup

AU - Jeon, Min Jae

AU - Kim, Eun Hee

AU - Lee, Myung Shik

AU - Karin, Michael

AU - Baik, Ja-Hyun

AU - Park, Joong Yeol

AU - Lee, Ki Up

AU - Kim, Young Bum

AU - Kim, Min Seon

PY - 2010/3/26

Y1 - 2010/3/26

N2 - 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 proopiomelanocortin (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 POMCneurons. 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.

AB - 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 proopiomelanocortin (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 POMCneurons. 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.

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