Nuclear factor κB (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter.
OBJECTIVE
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
Our study provides a mechanism for the involvement of RELA in the divergent regulation of energy homeostasis in acute and chronic inflammation.
Singapore Bioimaging Consortium, Agency for Science, Technology and Research, #02-02 Helios, 11 Biopolis Way, Singapore 138667, Republic of Singapore.
X
X
Shi
X
X
Wang
Q
Q
Li
M
M
Su
E
E
Chew
E T
ET
Wong
Z
Z
Lacza
G K
GK
Radda
V
V
Tergaonkar
W
W
Han
D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal; D004435:Eating; D005247:Feeding Behavior; D005786:Gene Expression Regulation; D007249:Inflammation; D020738:Leptin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D020738:Leptin; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D011333:Pro-Opiomelanocortin