RelA Governs a Network of Islet-Specific Metabolic Genes Necessary for Beta-Cell Function

Abstract

NF-κB activation unites metabolic and inflammatory responses in many diseases yet less is known about the role NF-κB plays in normal metabolism. Here, to define this role in the context of beta cell function and metabolic control, we deleted the canonical NF-κB transcription factor RelA/p65 specifically in pancreatic beta cells to generate βP65KO mice. RelA deficiency resulted in complete loss of stimulus dependent inflammatory gene upregulation, consistent with its known role to govern inflammation. However, RelA deletion also rendered mice glucose intolerant due to a functional loss of insulin secretion. Glucose intolerance was intrinsic to beta cells as βP65KO islets failed to secrete insulin ex vivo in response to a glucose challenge, and were unable to restore metabolic control when transplanted into secondary diabetic recipients. Maintenance of glucose tolerance required RelA, but was independent of classical NF-κB inflammatory cascades, as blocking NF-κB signalling in vivo by beta cell knock-out of the essential activator of NF-κB, NEMO, or beta cell overexpression of the negative NF-κB regulator, A20, did not cause severe glucose intolerance. Thus, basal RelA activity performs an essential and islet-intrinsic role to maintain normal glucose homeostasis. Genome wide bioinformatic mapping revealed the presence of RelA binding sites in the promoter regions of specific metabolic genes, and in the majority (~70%) of islet enhancer hubs that are responsible for shaping beta cell type-specific gene expression programmes. Indeed, islet specific metabolic genes Slc2a2 and Capn9, identified within the large network of islet enhancer hub genes showed dysregulated expression in βP65KO islets. These data demonstrate an unappreciated role for RelA as a regulator of islet-specific transcriptional programmes necessary for the maintenance of healthy glucose metabolism.