Nuclear factor κb (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter

X. Shi, X. Wang, Q. Li, M. Su, E. Chew, E. T. Wong, Z. Lacza, G. K. Radda, V. Tergaonkar, W. Han

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Aims/hypothesis: While chronic low-grade inflammation is associated with obesity, acute inflammation reduces food intake and leads to negative energy balance. Although both types of inflammation activate nuclear factor κB (NF-κB) signalling, it remains unclear how NF-κB activation results in opposite physiological responses in the two types of inflammation. The goal of this study was to address this question, and to understand the link between inflammation and leptin signalling. Methods: We studied the ability of NF-κB to modulate Pomc transcription, and how it impinges on signal transducer and activator of transcription 3 (STAT3)-mediated leptin signalling by using a combination of animal models, biochemical assays and molecular biology. Results: We report that suppression of food intake and physical movement with acute inflammation is not dependent on STAT3 activation in pro-opiomelanocortin (POMC) neurons. Under these conditions, activated NF-κB independently leads to increased Pomc transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) experiments reveal that NF-κB v-rel reticuloendotheliosis viral oncogene homologue A (avian) (RELA [also known as p65]) binds to the Pomc promoter region between -138 and -88 bp, which also harbours the trans-acting transcription factor 1 (SP1) binding site. We found significant changes in the methylation pattern at this region and reduced Pomc activation under chronic inflammation induced by a high-fat diet. Furthermore, RELA is unable to bind and activate transcription when the Pomc promoter is methylated. Finally, RELA binds to STAT3 and inhibits STAT3-mediated promoter activity, suggesting that RELA, possibly together with forkhead box-containing protein 1 (FOXO1), may prevent STAT3-mediated leptin activation of the Pomc promoter. Conclusions/interpretation: Our study provides a mechanism for the involvement of RELA in the divergent regulation of energy homeostasis in acute and chronic inflammation.

Original languageEnglish
Pages (from-to)925-936
Number of pages12
JournalDiabetologia
Volume56
Issue number4
DOIs
Publication statusPublished - Apr 2013

Fingerprint

Energy Metabolism
STAT3 Transcription Factor
Eating
Inflammation
Leptin
Transcription Factor RelA
Forkhead Transcription Factors
Pro-Opiomelanocortin
Trans-Activators
Chromatin Immunoprecipitation
High Fat Diet
Electrophoretic Mobility Shift Assay
Genetic Promoter Regions
Methylation
Transcriptional Activation
Molecular Biology
Homeostasis
Transcription Factors
Animal Models
Obesity

Keywords

  • Appetite
  • Energy homeostasis
  • FOXO1
  • Inflammation
  • NF-κB
  • Obesity
  • STAT3

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Nuclear factor κb (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter. / Shi, X.; Wang, X.; Li, Q.; Su, M.; Chew, E.; Wong, E. T.; Lacza, Z.; Radda, G. K.; Tergaonkar, V.; Han, W.

In: Diabetologia, Vol. 56, No. 4, 04.2013, p. 925-936.

Research output: Contribution to journalArticle

Shi, X, Wang, X, Li, Q, Su, M, Chew, E, Wong, ET, Lacza, Z, Radda, GK, Tergaonkar, V & Han, W 2013, 'Nuclear factor κb (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter', Diabetologia, vol. 56, no. 4, pp. 925-936. https://doi.org/10.1007/s00125-013-2831-2
Shi, X. ; Wang, X. ; Li, Q. ; Su, M. ; Chew, E. ; Wong, E. T. ; Lacza, Z. ; Radda, G. K. ; Tergaonkar, V. ; Han, W. / Nuclear factor κb (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter. In: Diabetologia. 2013 ; Vol. 56, No. 4. pp. 925-936.
@article{2e5cfce6f91a442eb99e8cf7e66076f8,
title = "Nuclear factor κb (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter",
abstract = "Aims/hypothesis: While chronic low-grade inflammation is associated with obesity, acute inflammation reduces food intake and leads to negative energy balance. Although both types of inflammation activate nuclear factor κB (NF-κB) signalling, it remains unclear how NF-κB activation results in opposite physiological responses in the two types of inflammation. The goal of this study was to address this question, and to understand the link between inflammation and leptin signalling. Methods: We studied the ability of NF-κB to modulate Pomc transcription, and how it impinges on signal transducer and activator of transcription 3 (STAT3)-mediated leptin signalling by using a combination of animal models, biochemical assays and molecular biology. Results: We report that suppression of food intake and physical movement with acute inflammation is not dependent on STAT3 activation in pro-opiomelanocortin (POMC) neurons. Under these conditions, activated NF-κB independently leads to increased Pomc transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) experiments reveal that NF-κB v-rel reticuloendotheliosis viral oncogene homologue A (avian) (RELA [also known as p65]) binds to the Pomc promoter region between -138 and -88 bp, which also harbours the trans-acting transcription factor 1 (SP1) binding site. We found significant changes in the methylation pattern at this region and reduced Pomc activation under chronic inflammation induced by a high-fat diet. Furthermore, RELA is unable to bind and activate transcription when the Pomc promoter is methylated. Finally, RELA binds to STAT3 and inhibits STAT3-mediated promoter activity, suggesting that RELA, possibly together with forkhead box-containing protein 1 (FOXO1), may prevent STAT3-mediated leptin activation of the Pomc promoter. Conclusions/interpretation: Our study provides a mechanism for the involvement of RELA in the divergent regulation of energy homeostasis in acute and chronic inflammation.",
keywords = "Appetite, Energy homeostasis, FOXO1, Inflammation, NF-κB, Obesity, STAT3",
author = "X. Shi and X. Wang and Q. Li and M. Su and E. Chew and Wong, {E. T.} and Z. Lacza and Radda, {G. K.} and V. Tergaonkar and W. Han",
year = "2013",
month = "4",
doi = "10.1007/s00125-013-2831-2",
language = "English",
volume = "56",
pages = "925--936",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - Nuclear factor κb (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter

AU - Shi, X.

AU - Wang, X.

AU - Li, Q.

AU - Su, M.

AU - Chew, E.

AU - Wong, E. T.

AU - Lacza, Z.

AU - Radda, G. K.

AU - Tergaonkar, V.

AU - Han, W.

PY - 2013/4

Y1 - 2013/4

N2 - Aims/hypothesis: While chronic low-grade inflammation is associated with obesity, acute inflammation reduces food intake and leads to negative energy balance. Although both types of inflammation activate nuclear factor κB (NF-κB) signalling, it remains unclear how NF-κB activation results in opposite physiological responses in the two types of inflammation. The goal of this study was to address this question, and to understand the link between inflammation and leptin signalling. Methods: We studied the ability of NF-κB to modulate Pomc transcription, and how it impinges on signal transducer and activator of transcription 3 (STAT3)-mediated leptin signalling by using a combination of animal models, biochemical assays and molecular biology. Results: We report that suppression of food intake and physical movement with acute inflammation is not dependent on STAT3 activation in pro-opiomelanocortin (POMC) neurons. Under these conditions, activated NF-κB independently leads to increased Pomc transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) experiments reveal that NF-κB v-rel reticuloendotheliosis viral oncogene homologue A (avian) (RELA [also known as p65]) binds to the Pomc promoter region between -138 and -88 bp, which also harbours the trans-acting transcription factor 1 (SP1) binding site. We found significant changes in the methylation pattern at this region and reduced Pomc activation under chronic inflammation induced by a high-fat diet. Furthermore, RELA is unable to bind and activate transcription when the Pomc promoter is methylated. Finally, RELA binds to STAT3 and inhibits STAT3-mediated promoter activity, suggesting that RELA, possibly together with forkhead box-containing protein 1 (FOXO1), may prevent STAT3-mediated leptin activation of the Pomc promoter. Conclusions/interpretation: Our study provides a mechanism for the involvement of RELA in the divergent regulation of energy homeostasis in acute and chronic inflammation.

AB - Aims/hypothesis: While chronic low-grade inflammation is associated with obesity, acute inflammation reduces food intake and leads to negative energy balance. Although both types of inflammation activate nuclear factor κB (NF-κB) signalling, it remains unclear how NF-κB activation results in opposite physiological responses in the two types of inflammation. The goal of this study was to address this question, and to understand the link between inflammation and leptin signalling. Methods: We studied the ability of NF-κB to modulate Pomc transcription, and how it impinges on signal transducer and activator of transcription 3 (STAT3)-mediated leptin signalling by using a combination of animal models, biochemical assays and molecular biology. Results: We report that suppression of food intake and physical movement with acute inflammation is not dependent on STAT3 activation in pro-opiomelanocortin (POMC) neurons. Under these conditions, activated NF-κB independently leads to increased Pomc transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) experiments reveal that NF-κB v-rel reticuloendotheliosis viral oncogene homologue A (avian) (RELA [also known as p65]) binds to the Pomc promoter region between -138 and -88 bp, which also harbours the trans-acting transcription factor 1 (SP1) binding site. We found significant changes in the methylation pattern at this region and reduced Pomc activation under chronic inflammation induced by a high-fat diet. Furthermore, RELA is unable to bind and activate transcription when the Pomc promoter is methylated. Finally, RELA binds to STAT3 and inhibits STAT3-mediated promoter activity, suggesting that RELA, possibly together with forkhead box-containing protein 1 (FOXO1), may prevent STAT3-mediated leptin activation of the Pomc promoter. Conclusions/interpretation: Our study provides a mechanism for the involvement of RELA in the divergent regulation of energy homeostasis in acute and chronic inflammation.

KW - Appetite

KW - Energy homeostasis

KW - FOXO1

KW - Inflammation

KW - NF-κB

KW - Obesity

KW - STAT3

UR - http://www.scopus.com/inward/record.url?scp=84876490508&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876490508&partnerID=8YFLogxK

U2 - 10.1007/s00125-013-2831-2

DO - 10.1007/s00125-013-2831-2

M3 - Article

C2 - 23370526

AN - SCOPUS:84876490508

VL - 56

SP - 925

EP - 936

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 4

ER -