On the Immunometabolic Role of NF-κB in Adipocytes

Two decades of research have established that Nuclear Factor-κB (NF-κB) signaling plays a critical role in reprogramming the fat cell transcriptome towards inflammation in response to overnutrition and metabolic stress. Several groups have suggested that inhibition of NF-κB signaling could have metabolic benefits for obesity-associated adipose tissue inflammation. However, two significant problems arise with this approach. The first is how to deliver general NF-κB inhibitors into adipocytes without allowing these compounds to disrupt normal functioning in cells of the immune system. The second issue is that general inhibition of canonical NF-κB signaling in adipocytes will likely lead to a massive increase in adipocyte apoptosis under conditions of metabolic stress, leading full circle into a secondary inflammation (However, this problem may not be true for non-canonical NF-κB signaling.). This review will focus on the research that has examined canonical and non-canonical NF-κB signaling in adipocytes, focusing on genetic studies that examine loss-of-function of NF-κB specifically in fat cells. Although the development of general inhibitors of canonical NF-κB signaling seems unlikely to succeed in alleviating adipose tissue inflammation in humans, the door remains open for more targeted therapeutics. In principle, these would include compounds that interrogate NF-κB DNA binding, protein-protein interactions, or post-translational modifications that partition NF-κB activity towards some genes and away from others in adipocytes. I also discuss the possibility for inhibitors of non-canonical NF-κB signaling to realize success in mitigating fat cell dysfunction in obesity. To plant the seeds for such approaches, much biochemical “digging” in adipocytes remains; this includes identifying—in an unbiased manner–NF-κB direct and indirect targets, genomic DNA binding sites for all five NF-κB subunits, NF-κB protein-protein interactions, and post-translational modifications of NF-κB in fat cells.