Mutual regulation of metabolic processes and proinflammatory NF-κB signaling
Authors: Michael Kracht, Ulf Müller-Ladner, M. Lienhard Schmitz
Journal: Journal of Allergy and Clinical Immunology (2020)

The nuclear factor kappa B (NF-κB) signaling system, a key regulator of immunologic processes, also affects a plethora of metabolic changes associated with inflammation and the immune response. NF-κB–regulating signaling cascades, in concert with NF-κB–mediated transcriptional events, control the metabolism at several levels. NF-κB 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-κB activity, thereby creating a highly connected regulatory network. These insights have resulted in the identification of the noncanonical IκB kinase kinases IκB kinase ɛ 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-κB pathway components improves glucose homeostasis in a subset of patients with type 2 diabetes. The nuclear factor kappa B (NF-κB) signaling system, a key regulator of immunologic processes, also affects a plethora of metabolic changes associated with inflammation and the immune response. NF-κB–regulating signaling cascades, in concert with NF-κB–mediated transcriptional events, control the metabolism at several levels. NF-κB 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-κB activity, thereby creating a highly connected regulatory network. These insights have resulted in the identification of the noncanonical IκB kinase kinases IκB kinase ɛ 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-κB pathway components improves glucose homeostasis in a subset of patients with type 2 diabetes. Inflammatory processes (including fever) are accompanied by an increased metabolical demand and thus require the reversible adjustment of metabolic programs, either locally or systemically.1Fitzgerald K.A. Kagan J.C. Toll-like receptors and the control of immunity.Cell. 2020; 180: 1044-1066Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,2Ganeshan K. Chawla A. Metabolic regulation of immune responses.Annu Rev Immunol. 2014; 32: 609-634Crossref PubMed Scopus (262) Google Scholar Although metabolic pathways have an impact on the effector functions of specific immune and nonimmune cells, vice versa immunologically relevant signaling proteins contribute to the rewiring of metabolic checkpoints. The mutual crossregulation between immunologic and metabolic circuits is also reflected at the level of individual proteins, which can have a dual function in both processes. A prototype example is the ubiquitin E3 ligase TNF receptor–associated factor 6, which participates in proinflammatory signaling downstream of IL-1– and Toll-like receptors, but also promotes autophagy by enabling phagophore formation via K63-linked polyubiquitination of ULK1 (Unc-51 like autophagy activating kinase 1) and coiled-coil myosin-like BCL2-interacting protein.3Nazio F. Strappazzon F. Antonioli M. Bielli P. Cianfanelli V. Bordi M. et al.mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6.Nat Cell Biol. 2013; 15: 406-416Crossref PubMed Scopus (403) Google Scholar,4Shi C.S. Kehrl J.H. TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1 to control TLR4-induced autophagy.Sci Signal. 2010; 3: ra42Crossref PubMed Scopus (288) Google Scholar TNF receptor–associated factor 6 activity also contributes to the activation of the NF-κB transcription factor system in response to many inflammatory signals.5Wu H. Arron J.R. TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology.Bioessays. 2003; 25: 1096-1105Crossref PubMed Scopus (214) Google Scholar NF-κB is a collective name for an evolutionary conserved family of 5 different transcription factors that can form homodimers or heterodimers to reprogram the inflammatory gene response.6Hayden M.S. Ghosh S. NF-kappaB, the first quarter-century: remarkable progress and outstanding questions.Genes Dev. 2012; 26: 203-234Crossref PubMed Scopus (999) Google Scholar,7Lawrence T. The nuclear factor NF-kappaB pathway in inflammation.Cold Spring Harb Perspect Biol. 2009; 1: a001651Crossref PubMed Scopus (1772) Google Scholar Although proinflammatory gene expression is orchestrated by many different transcription factors including members of the activator protein 1, nuclear factor of activated T cells, and signal transducer and activator of transcription family, the transcription of most genes induced by cytokines such as IL-1 or TNF depends on NF-κB.8Kempe S. Kestler H. Lasar A. Wirth T. NF-kappaB controls the global pro-inflammatory response in endothelial cells: evidence for the regulation of a pro-atherogenic program.Nucleic Acids Res. 2005; 33: 5308-5319Crossref PubMed Scopus (186) Google Scholar,9Riedlinger T. Liefke R. Meier-Soelch J. Jurida L. Nist A. Stiewe T. et al.NF-kappaB p65 dimerization and DNA-binding is important for inflammatory gene expression.FASEB J. 2019; 33: 4188-4202Crossref PubMed Scopus (4) Google Scholar The broad relevance of NF-κB for immune signaling has been revealed by many studies using genetically engineered mice and also by the association of NF-κB mutations with inflammatory diseases, as described in several excellent reviews.10Senegas A. Gautheron J. Maurin A.G. Courtois G. IKK-related genetic diseases: probing NF-kappaB functions in humans and other matters.Cell Mol Life Sci. 2015; 72: 1275-1287Crossref PubMed Scopus (0) Google Scholar,11Zhang Q. Lenardo M.J. Baltimore D. 30 years of NF-kappaB: a blossoming of relevance to human pathobiology.Cell. 2017; 168: 37-57Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar Given the central relevance of NF-κB signaling pathways for innate and parts of the adaptive immunity, we will focus in this review on the mutual regulation of metabolic processes and the NF-κB signaling pathways. Evolutionary, the NF-κB signaling system is quite ancient as it is already present in insects, arthropods, and even sponges.12Wang X.W. Tan N.S. Ho B. Ding J.L. Evidence for the ancient origin of the NF-kappaB/IkappaB cascade: its archaic role in pathogen infection and immunity.Proc Natl Acad Sci U S A. 2006; 103: 4204-4209Crossref PubMed Scopus (0) Google Scholar,13Williams L.M. Inge M.M. Mansfield K.M. Rasmussen A. Afghani J. Agrba M. et al.Transcription factor NF-kappaB in a basal metazoan, the sponge, has conserved and unique sequences, activities, and regulation.Dev Comp Immunol. 2020; 104: 103559Crossref PubMed Scopus (0) Google Scholar Initially developed by evolution to rapidly cope with life-threatening situations, NF-κB signaling pathways became more diverged in vertebrates and were used as central effectors for the activation and differentiation of immune cells. These NF-κB–mediated regulatory processes not only affect differentiation, proliferation, migration, and survival but also the metabolic state of cells. To fulfill this body of different tasks, the NF-κB system uses a combinatorial pattern of 5 different DNA-binding subunits, which all harbor an N-terminal NF-κB/Rel homology domain mediating dimerization and DNA binding. Three of the subunits, that is, RELA (also known as p65), RELB, and REL (also known as c-Rel), contain C-terminal transactivation domains, which are important for transcriptional activation.14Perkins N.D. Integrating cell-signalling pathways with NF-kappaB and IKK function.Nat Rev Mol Cell Biol. 2007; 8: 49-62Crossref PubMed Scopus (1711) Google Scholar Two of the family members, namely, NF-κB2 (also known as p100/p52) and NF-κB1 (also known as p105/p50), are derived from precursor proteins through phosphorylation-induced partial proteolysis or during translation to yield the DNA-binding forms p50 and p52, respectively.15Perkins N.D. The diverse and complex roles of NF-kappaB subunits in cancer.Nat Rev Cancer. 2012; 12: 121-132Crossref PubMed Scopus (537) Google Scholar The p50 and p52 proteins lack transactivation domains and can induce gene expression only on dimerization with transactivation domain–containing NF-κB family members.16Riedlinger T. Haas J. Busch J. van de Sluis B. Kracht M. Schmitz M.L. The direct and indirect roles of NF-kappaB in cancer: lessons from oncogenic fusion proteins and knock-in mice.Biomedicines. 2018; 6: 36Crossref Scopus (9) Google Scholar Only a few cell types such as B cells, Sertoli cells, and neurons show constitutive NF-κB activity, whereas most cell types inactivate this transcription factor through the interaction with inhibitory IκB proteins, which trap the DNA-binding subunits in the cytosol.17Oeckinghaus A. Ghosh S. The NF-kappaB family of transcription factors and its regulation.Cold Spring Harb Perspect Biol. 2009; 1: a000034Crossref PubMed Scopus (1086) Google Scholar Therefore, the principal step of NF-κB activation requires the proteolytic elimination of IκBs and the subsequent liberation of the DNA-binding dimer as a prerequisite for the induction of gene expression, which can occur in various kinetics, as schematically illustrated in Fig 1, A. Induction by a pulsed stimulus results in a single peak of high NF-κB activity and gene expression, whereas persistent stimulation leads to an oscillatory response, due to the induction of distinct feedback mechanisms at staggered time points.18Hoffmann A. Levchenko A. Scott M.L. Baltimore D. The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation.Science. 2002; 298: 1241-1245Crossref PubMed Scopus (1362) Google Scholar,19Renner F. Schmitz M.L. Autoregulatory feedback loops terminating the NF-kappaB response.Trends Biochem Sci. 2009; 34: 128-135Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar The persistent administration of a weak or low-dose NF-κB trigger often results in a continuous low-grade activation, which is considered to be specifically relevant in chronic and smoldering inflammation, and in the (constitutive) regulation of metabolic processes. At the single-cell level, these various activation states are not phased in and can exist side by side, creating an even larger repertoire of fine-tuning and timing of NF-κB responses.20Mayr-Buro C. Schlereth E. Beuerlein K. Tenekeci U. Meier-Soelch J. Schmitz M.L. et al.Single-cell analysis of multiple steps of dynamic NF-kappaB regulation in interleukin-1alpha-triggered tumor cells using proximity ligation assays.Cancers (Basel). 2019; 11: 1199Crossref Scopus (1) Google Scholar NF-κB activation in response to DNA damage proceeds by the atypical activation pathway, whereas immunologically relevant induction steps proceed via into the canonical and noncanonical NF-κB signaling pathways.21Liu T. Zhang L. Joo D. Sun S.C. NF-kappaB signaling in inflammation.Signal Transduct Target Ther. 2017; 2: 17023Crossref PubMed Scopus (1023) Google Scholar The canonical pathway is triggered by receptors sensing molecular patterns or by cytokine receptors, and the respective signal transduction proceeds by the regulated assembly of adapter proteins and enzymes mediating posttranslational modifications including ubiquitination and phosphorylation. Activation of the canonical NF-κB signaling pathway by stimulation of Toll-like receptors leads to the myeloid differentiation factor 88–dependent activation of IL-1 receptor–associated kinase kinases, which in turn activate the ubiquitin E3 ligase TNF receptor–associated factor 6, thus resulting in the activation of the so-called IκB kinase (IKK) complex.22Muroi M. Tanamoto K.I. TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-kappaB.J Leukoc Biol. 2008; 83: 702-707Crossref PubMed Scopus (0) Google Scholar,23Verstrepen L. Beyaert R. Receptor proximal kinases in NF-kappaB signaling as potential therapeutic targets in cancer and inflammation.Biochem Pharmacol. 2014; 92: 519-529Crossref PubMed Scopus (0) Google Scholar This protein complex consists of the scaffold protein NEMO (NF-κB essential modifier)/IKKγ and the kinases IKKα and IKKβ, which phosphorylate IκBα proteins and thus enable the IκB modification by K48-branched ubiquitin chains and proteasome-dependent proteolysis.24Alkalay I. Yaron A. Hatzubai A. Orian A. Ciechanover A. Ben-Neriah Y. Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway.Proc Natl Acad Sci U S A. 1995; 92: 10599-10603Crossref PubMed Scopus (0) Google Scholar NEMO is also modified by linear ubiquitin chains, which are generated by an E3 ligase complex called the linear ubiquitin chain assembly complex containing the proteins HOIL-1L interacting protein (HOIP), HOIL-1L, and Sharpin.25Tokunaga F. Sakata S. Saeki Y. Satomi Y. Kirisako T. Kamei K. et al.Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation.Nat Cell Biol. 2009; 11: 123-132Crossref PubMed Scopus (626) Google Scholar Linear ubiquitin chain assembly complex–mediated linear ubiquitination is important for NF-κB activation; accordingly, the knockout of HOIP causes embryonic lethality owing to deregulation of TNF receptor 1–mediated cell death.26Peltzer N. Darding M. Montinaro A. Draber P. Draberova H. Kupka S. et al.LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis.Nature. 2018; 557: 112-117Crossref PubMed Scopus (64) Google Scholar The noncanonical pathway is independent from the IKK complex and IκB and requires NF-κB–inducing kinase, which activates IKKα to phosphorylate the p100/NF-κB2 precursor protein, leading to its processing to p52.27Senftleben U. Cao Y. Xiao G. Greten F.R. Krahn G. Bonizzi G. et al.Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway.Science. 2001; 293: 1495-1499Crossref PubMed Scopus (1033) Google Scholar,28Xiao G. Fong A. Sun S.C. Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation.J Biol Chem. 2004; 279: 30099-30105Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar This process leads to the formation of p52/RelB and p50/RelB dimers, which serve to trigger target gene expression.29Bonizzi G. Bebien M. Otero D.C. Johnson-Vroom K.E. Cao Y. Vu D. et al.Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers.EMBO J. 2004; 23: 4202-4210Crossref PubMed Scopus (261) Google Scholar This activation pathway is activated in response to a distinct class of stimuli, particularly in B cells, and proceeds with much slower kinetics.28Xiao G. Fong A. Sun S.C. Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation.J Biol Chem. 2004; 279: 30099-30105Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar In addition, the IKK kinase family includes the noncanonical family members TBK1 (TANK-binding kinase 1) and IKKε, which are involved in various processes including immune signaling, autophagy, cell proliferation, and survival as well as metabolism.30Durand J.K. Zhang Q. Baldwin A.S. Roles for the IKK-related kinases TBK1 and IKKepsilon in cancer.Cells. 2018; 7: 139Crossref PubMed Google Scholar Inflammatory stimuli can increase the mRNA and protein levels of both kinases, and their enzymatic activity can additionally be triggered either by transautophosphorylation or by association with adapter proteins or upstream kinases such as ULK1.31Clark K. Plater L. Peggie M. Cohen P. Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation.J Biol Chem. 2009; 284: 14136-14146Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 32Ma X. Helgason E. Phung Q.T. Quan C.L. Iyer R.S. Lee M.W. et al.Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation.Proc Natl Acad Sci U S A. 2012; 109: 9378-9383Crossref PubMed Scopus (106) Google Scholar, 33Saul V.V. Seibert M. Kruger M. Jeratsch S. Kracht M. Schmitz M.L. ULK1/2 restricts the formation of inducible SINT-speckles, membraneless organelles controlling the threshold of TBK1 activation.iScience. 2019; 19: 527-544Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 34Zhao P. Wong K.I. Sun X. Reilly S.M. Uhm M. Liao Z. et al.TBK1 at the crossroads of inflammation and energy homeostasis in adipose tissue.Cell. 2018; 172: 731-743Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar The noncanonical IKKs are dispensable for IκB phosphorylation but instead are important for phosphorylation of the DNA-binding subunits and control of NF-κB transcriptional activity.35tenOever B.R. Ng S.L. Chua M.A. McWhirter S.M. Garcia-Sastre A. Maniatis T. Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity.Science. 2007; 315: 1274-1278Crossref PubMed Scopus (246) Google Scholar The IKK-related kinases also serve as part of a negative feedback loop by phosphorylating the canonical IKKs and NEMO, which results in reduced IKKα/β activity and NF-κB–dependent gene transcription.36Clark K. Takeuchi O. Akira S. Cohen P. The TRAF-associated protein TANK facilitates cross-talk within the IkappaB kinase family during Toll-like receptor signaling.Proc Natl Acad Sci U S A. 2011; 108: 17093-17098Crossref PubMed Scopus (0) Google Scholar TBK1 is activated by pattern-recognition receptors and mediates IFN regulatory factor 3/7–dependent activation of type I IFN expression. IKKε also protects from DNA damage–induced cell death37Renner F. Moreno R. Schmitz M.L. SUMOylation-dependent localization of IKKepsilon in PML nuclear bodies is essential for protection against DNA-damage-triggered cell death.Mol Cell. 2010; 37: 503-515Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and contributes to the late phase of the NF-κB–mediated transcription by various mechanisms including p65 phosphorylation.38Mattioli I. Geng H. Sebald A. Hodel M. Bucher C. Kracht M. et al.Inducible phosphorylation of NF-kappa B p65 at serine 468 by T cell costimulation is mediated by IKK epsilon.J Biol Chem. 2006; 281: 6175-6183Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,39Buss H. Dorrie A. Schmitz M.L. Hoffmann E. Resch K. Kracht M. Constitutive and interleukin-1-inducible phosphorylation of p65 NF-{kappa}B at serine 536 is mediated by multiple protein kinases including I{kappa}B kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription.J Biol Chem. 2004; 279: 55633-55643Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar The canonical and noncanonical NF-κB signaling pathways and their crosstalk with atypical IKKs is schematically summarized in Fig 1, B. In line with its role as a central signaling hub and stress sensor, NF-κB is activated by a bewildering number of different conditions. These mainly involve inflammatory (and infectious) triggers, but also other signals such as hypoxia, DNA damage, oxidative stress, endoplasmic reticulum stress, and (with the exception of heat shock) probably every condition representing a menacing situation.40Hoesel B. Schmid J.A. The complexity of NF-kappaB signaling in inflammation and cancer.Mol Cancer. 2013; 12: 86Crossref PubMed Scopus (1517) Google Scholar,41Schmitz M.L. Shaban M.S. Albert B.V. Gokcen A. Kracht M. The crosstalk of endoplasmic reticulum (ER) stress pathways with NF-kappaB: complex mechanisms relevant for cancer, inflammation and infection.Biomedicines. 2018; 6: 58Crossref PubMed Scopus (0) Google Scholar Activated NF-κB, in turn, enables the cell to cope with these endangering situations, a feature that is shared with further stress-sensing transcription factors such as p53 and hypoxia-inducible factor 1α. Although the role of p53 and hypoxia-inducible factor 1α as master regulators of metabolic homeostasis in unstressed cells is well established,42Puzio-Kuter A.M. The role of p53 in metabolic regulation.Genes Cancer. 2011; 2: 385-391Crossref PubMed Scopus (137) Google Scholar,43Semenza G.L. Regulation of metabolism by hypoxia-inducible factor 1.Cold Spring Harb Symp Quant Biol. 2011; 76: 347-353Crossref PubMed Scopus (199) Google Scholar the function of NF-κB for the regulation of metabolic processes is different for several reasons: (1) NF-κB does not appear to play a major role in homeostasis of metabolism but rather becomes important in response to perturbations in immune signaling or situations of overnutrition or undernutrition; (2) the role of the NF-κB system for metabolic regulation reaches beyond its ability to function as a transcription factor leading to transcriptional gene expression changes. Apparently, upstream regulators of NF-κB in the cytoplasm can also directly target metabolic factors as discussed later; (3) the contribution of NF-κB to metabolic reprogramming might be primarily be relevant in disease conditions such as inflammation or cancer, in which cells undergo a profound change and rewiring of metabolic programs.44Christ A. Lauterbach M. Latz E. Western diet and the immune system: an inflammatory connection.Immunity. 2019; 51: 794-811Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,45Vander Heiden M.G. DeBerardinis R.J. Understanding the intersections between metabolism and cancer biology.Cell. 2017; 168: 657-669Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar In this context, it is important to note that humans with loss-of-function mutations in components of the NF-κB core pathway typically suffer from alterations in cell proliferation, inadequate responses to infections, a compromised development, or differentiation of immune cells and aggravated inflammatory conditions. However, there is lack of data revealing long-term changes in metabolism in patients with defined genetic defects in the NF-κB system.46Zhong Z. Umemura A. Sanchez-Lopez E. Liang S. Shalapour S. Wong J. et al.NF-kappaB restricts inflammasome activation via elimination of damaged mitochondria.Cell. 2016; 164: 896-910Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar Here, as outlined in detail later, we will discuss the mutual impact and crossregulation between the proinflammatory NF-κB signaling system and metabolic processes derived from cellular and preclinical models as a future route to more detailed investigations of human patients. Increasing evidence shows that NF-κB can regulate insulin and glucagon signaling, thus indirectly affecting many metabolic pathways, as depicted in Fig 2, A. Insulin is a peptide hormone that is released from pancreatic β cells. On binding to its cognate insulin receptor, it stimulates the signaling cascades required for the uptake of glucose, the metabolic conversion of glucose to pyruvate, and lipogenesis.47Haeusler R.A. McGraw T.E. Accili D. Biochemical and cellular properties of insulin receptor signalling.Nat Rev Mol Cell Biol. 2018; 19: 31-44Crossref PubMed Scopus (121) Google Scholar In the β cell, elevated glucose levels lead to increased Ca2+ levels and increased NF-κB activity, which in turn contribute to the release of insulin. Attenuation of NF-κB activation in β cells by overexpression of a nondegradable form of IκBα results in impaired glucose-stimulated insulin secretion.48Norlin S. Ahlgren U. Edlund H. Nuclear factor-{kappa}B activity in {beta}-cells is required for glucose-stimulated insulin secretion.Diabetes. 2005; 54: 125-132Crossref PubMed Scopus (0) Google Scholar However, overexpression of this mutant form of IκBα protects β cells from inflammation-triggered cell death.49Eldor R. Yeffet A. Baum K. Doviner V. Amar D. Ben-Neriah Y. et al.Conditional and specific NF-kappaB blockade protects pancreatic beta cells from diabetogenic agents.Proc Natl Acad Sci U S A. 2006; 103: 5072-5077Crossref PubMed Scopus (184) Google Scholar Likewise, a cell-penetrating peptide disrupting the IKK-NEMO interaction also blocks IL-1–induced β-cell death.50Rehman K.K. Bertera S. Bottino R. Balamurugan A.N. Mai J.C. Mi Z. et al.Protection of islets by in situ peptide-mediated transduction of the Ikappa B kinase inhibitor Nemo-binding domain peptide.J Biol Chem. 2003; 278: 9862-9868Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar These data suggest that interference with exaggerated NF-κB activity in β cells can prevent their death and thus protect from the onset of type 1 diabetes. In type 2 diabetes, overnutrition such as a high-fat diet (HFD) triggers a NF-κB–mediated chronic and subacute inflammation that renders the tissue cells less responsive to insulin signaling. In this process, fatty acids can be absorbed and converted to diacylglycerol, a known activator of protein kinase C, which in turn causes B-cell lymphoma 10–mediated activation of NF-κB in hepatocytes.51Van Beek M. Oravecz-Wilson K.I. Delekta P.C. Gu S. Li X. Jin X. et al.Bcl10 links saturated fat overnutrition with hepatocellular NF-kB activation and insulin resistance.Cell Rep. 2012; 1: 444-452Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Similarly, B-cell lymphoma 10–deficient mice are protected from hepatic HFD-induced NF-κB activation and insulin resistance.51Van Beek M. Oravecz-Wilson K.I. Delekta P.C. Gu S. Li X. Jin X. et al.Bcl10 links saturated fat overnutrition with hepatocellular NF-kB activation and insulin resistance.Cell Rep. 2012; 1: 444-452Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar In line with these results, overexpression of a nondegradable form of IκBα or deletion of the gene encoding IKKβ protected mice from HFD-induced type 2 diabetes.52Arkan M.C. Hevener A.L. Greten F.R. Maeda S. Li Z.W. Long J.M. et al.IKK-beta links inflammation to obesity-induced insulin resistance.Nat Med. 2005; 11: 191-198Crossref PubMed Scopus (1347) Google Scholar,53Cai D. Yuan M. Frantz D.F. Melendez P.A. Hansen L. Lee J. et al.Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.Nat Med. 2005; 11: 183-190Crossref PubMed Scopus (1591) Google Scholar Another example is mice with a hepatocyte-specific deletion of NEMO, which were protected from the development of obesity-associated insulin resistance. However, in this model, NEMO deficiency synergized with HFD in the development of liver steatosis, which finally resulted in liver tumorigenesis.54Wunderlich F.T. Luedde T. Singer S. Schmidt-Supprian M. Baumgartl J. Schirmacher P. et al.Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis.Proc Natl Acad Sci U S A. 2008; 105: 1297-1302Crossref PubMed Scopus (0) Google Scholar Vice versa, another murine model used hepatic expression of constitutively active IKKβ to simulate the pathophysiological situation of constitutive NF-κB activity and smoldering inflammation in hepatocytes. These transgenic hepatocytes showed an increased cytokine signaling and insulin resistance.53Cai D. Yuan M. Frantz D.F. Melendez P.A. Hansen L. Lee J. et al.Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.Nat Med. 2005; 11: 183-190Crossref PubMed Scopus (1591) Google Scholar HFD also increases endoplasmic reticulum stress in the hypothalamus, which finally led to the activation of the IKK/NF-κB system. This in turn blunts the hypothalamic insulin and leptin signaling functions and finally causes energy imbalance and obesity.55Zhang X. Zhang G. Zhang H. Karin M. Bai H. Cai D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity.Cell. 2008; 135: 61-73Abstract Full Text Full Text PDF PubMed Scopus (891) Google Scholar The peptide hormone glucagon acts antagonistic to insulin and is released from pancreatic α cells. Binding to its cognate 7 transmembrane receptor leads to the adenylate cyclase–catalyzed generation of cyclic adenosine monophosphate (cAMP), which in turn triggers protein kinase A–mediated signaling pathways to promote gluconeogenesis and glycogenolysis. The levels of cAMP are reduced by degradation via phosphodiesterases such as phosphodiesterase 4B. The NF-κB subunit p52 binds to the phosphodiesterase 4B promoter and prevents its expression, thus allowing maintaining high cAMP levels. Accordingly, knockdown of p52 leads to increased phosphodiesterase 4B expression and lower cAMP levels, which in turn lowers glucagon-stimulated hyperglycemia.56Zhang W.S. Pan A. Zhang X. Ying A. Ma G. Liu B.L. et al.Inactivation of NF-kappaB2 (p52) restrains hepatic glucagon response via preserving PDE4B induction.Nat Commun. 2019; 10: 4303Crossref PubMed Scopus (1) Google Scholar Apical regulator