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

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

A central role for the mammalian target of rapamycin in LPS-induced anorexia in mice

“…administration of LPS activated hypothalamic NFkB by increasing the phosphorylation of the p65 subunit, the higher level of NFkB in the nucleus, and the upregulated expression of POMC may imply that the translocation of NFkB from cytoplasm into nucleus is related to the transcription of target genes such as POMC during LPS stimuli. These findings (Campo et al 2010, Jang et al 2010, Deshpande et al 2011 collectively imply that NFkB activation in the hypothalamus plays a critical role in LPS-induced anorexia.…”

“…A recent study has revealed that NFkB directly bound the POMC gene to promote transcription in response to LPS stimulation (Jang et al 2010), and meanwhile, the transcriptional level of NFkB was upregulated by LPS treatment in the hypothalamus. Nuclear translocation of NFkB has been shown to be insufficient for the maximal activation of NFkB (Chen & Greene 2004).…”

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

“…However, activation of hypothalamic NF-κB signalling can also promote Pomc transcription and induce weight loss and food intake reduction [24]. Moreover, constitutively active RELA triggers severe TNF-α-dependent inflammation, which leads to small sized and lean mice on a Tnfr1 (also known as Tnfrsf1a) −/− background [25].…”

Hypothalamic inflammation and food intake regulation during chronic illness

“…Acute inflammation leads to activation of POMC neurons [100], increased expression of MC4R [101] and increased POMC expression [102,103] as shown in models of LPS and IL-1␤ -induced anorexia. Consequently, counteracting the activation of the melanocortin system by MC4R antagonism prevented the development of LPS-induced anorexia [102,104,105].…”