Mutual regulation of metabolic processes and proinflammatory NF-κB signaling

Abstract

The nuclear factor kappa B (NF-kB) signaling system, a key regulator of immunologic processes, also affects a plethora of metabolic changes associated with inflammation and the immune response. NF-kB-regulating signaling cascades, in concert with NF-kB-mediated transcriptional events, control the metabolism at several levels. NF-kB modulates apical components of metabolic processes including metabolic hormones such as insulin and glucagon, the cellular master switches 5' AMP-activated protein kinase and mTOR, and also numerous metabolic enzymes and their respective regulators. Vice versa, metabolic enzymes and their products also exert multilevel control of NF-kB activity, thereby creating a highly connected regulatory network. These insights have resulted in the identification of the noncanonical IkB kinase kinases IkB kinase 3 and TBK1, which are upregulated by overnutrition, and may therefore be suitable potential therapeutic targets for metabolic syndromes. An inhibitor interfering with the activity of both kinases reduces obesity-related metabolic dysfunctions in mouse models and the encouraging results from a recent clinical trial indicate that targeting these NF-kB pathway components improves glucose homeostasis in a subset of patients with type 2 diabetes.

Genetic Variants of the NF-κB Pathway: Unraveling the Genetic Architecture of Psoriatic Disease

“…The NF-κB pathway is involved in the low-grade chronic inflammation associated with obesity. The noncanonical IkB kinase ε and TBK1 are upregulated by overnutrition and may therefore be suitable potential therapeutic targets for MetS [ 52 ]. Also, NF-κB modulates apical components of metabolic processes including metabolic hormones such as insulin and glucagon, and therefore this pathway is also involved in both insulin resistance and sensitivity, another key component of psoriatic disease-associated MetS [ 3 , 49 ].…”

Der Einfluss von Adipositas auf die Krankheitsaktivität bei entzündlich rheumatischen Erkrankungen

“…Ein weiteres dynamischeres Feld, welches derzeit intensiv beforscht wird, sind die Interaktionen zwischen dem Immunsystem und metabolischen Vorgängen [3,4], v. a. auch auf Ebene des Fettgewebes selbst [5][6][7]. In diese Interaktionen werden durch aktuelle Experimente und Da-ten zunehmend intra-wie extrazelluläre Signalmoleküle und Rezeptoren sowie weitere molekulare Mechanismen eingebracht, die von beiden, oft nicht als direkt in Bezug miteinander stehend gesehenen Systemen, genutzt werden.…”

“…Hierzu gehört, dass zahlreiche Rezeptoren an der Oberfläche von aktiven Zellen des Immunsystems existieren, die intrazellulär proentzündliche Genabschnitte mit der nachfolgenden Produktion von Entzündungsmolekülen aktivieren können [3,4]. Neben den bekannten Signalmolekülen Tumornekrosefaktor (TNF), Interleukin(IL)-1 und IL-6 sind v. a. die verschiedenen Adipozytokine, aber auch "rein metabolische" Moleküle wie Insulin, freie Fettsäuren und Zuckerverbindungen in der Lage, diese Entzündungsstoffwechselwege anzuschalten.…”

Monitoring the Levels of Cellular NF-κB Activation States

“…The first layer of NF-κB activity refers to the dynamic nature of the NF-κB system, which is never static and rather characterized by various activation states, as schematically shown in Figure 1 A. (i) In the constitutively active state, significant NF-κB activity is found in specific cell types such as Sertoli cells, B cells, hair follicle cells, and neurons [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. (ii) In the “high-ON” state, most of the NF-κB dimers are rapidly released from inhibitory IκB proteins and translocate to the nucleus.…”

“…The “high-ON” state is typical for fast and transient activation of the NF-κB system in response to proinflammatory triggers. (iii) In the “low-ON” state NF-κB shows a continuous low grade activation, as it often occurs in situations of smoldering inflammation or in the tumor microenvironment [ 26 , 27 , 28 , 29 , 30 , 31 ]. (iv) In the “OFF-state”, NF-κB is quantitatively trapped by IκB proteins in the cytosol and NF-κB-driven transcription is largely absent.…”