NF-κB, inflammation, and metabolic disease

Abstract

Metabolic disorders including obesity, type 2 diabetes, and atherosclerosis have been viewed historically as lipid storage disorders brought about by overnutrition. It is now widely appreciated that chronic low-grade inflammation plays a key role in the initiation, propagation, and development of metabolic diseases. Consistent with its central role in coordinating inflammatory responses, numerous recent studies have implicated the transcription factor NF-κB in the development of such diseases, thereby further establishing inflammation as a critical factor in their etiology and offering hope for the development of new therapeutic approaches for their treatment.

Figure 1. Inflammatory Triggers activate expression of pro-inflammatory genes through IKK and NF-κB

Following engagement of Toll-like receptors and cytokine receptors, signaling through MyD88 and death domain adapter molecules (respectively) and then via TRAFs results in phosphorylation of IKK and activation of the IKK complex kinase activity. NF-κB is constitutively bound to IκB molecules which confine its localization to the cytosol. IKK complex phosphorylation of serine residues on IκB promotes its polyubiquitination and degradation, thereby freeing NF-κB to enter the nucleus and activate transcription of target genes.

Figure 2. Overweight and obesity induces activation of inflammatory mediators in adipocytes and infiltrating macrophage cells

Metabolism of excess nutrients imposes stress on adipose tissue. Production of pro- inflammatory cytokines by adipocytes and adipocyte hypertrophy and expiration recruits M1 pro-inflammatory macrophages into the adipose tissue. Pro-inflammatory signaling in central nervous system and macrophage-derived cytokines promote systemic dysregulation of leptin signaling and perturbed energy balance.

Figure 3. TLR and ER stress responses in insulin resistance

Signaling from cytokine receptors and Toll-like receptors on the cell surface, as well as ER stress can activate the IKK complex and NF-κB to activate expression of pro-inflammatory cytokines and disable insulin signaling. Defective insulin signaling contributes to insulin resistance and the development of Type 2 diabetes.

Figure 4. Macrophage cells are central mediators of insulin resistance

Nutrient excess is sensed in peripheral metabolic tissues to result in production of pro- inflammatory cytokines IL-6, IL-1 and TNF-α. These cytokines drive macrophage activation and propagation of pro-inflammatory signals throughout the organism.

Figure 5. NF-κB mediates pro-inflammatory signaling in endothelia and leukocytes that drives atherogenesis

Pro-inflammatory signaling networks through NF-κB in vascular endothelia respond to deposition of oxidized lipoproteins by expression of adhesion molecules on the cell surface and leukocyte cytokines. Circulating monocytes are arrested at the site of inflammation and differentiate into cytokine-producing macrophage cells. Macrophage cells also consume lipids on the vascular wall swelling into foam cells that nucleate the atherosclerotic plaque. Continued recruitment, activation of leukocytes, lipid consumption and cell death results in the formation of a large atherosclerotic lesion impairing arterial blood flow and promoting thrombosis.