Nod1 Plays a Causal Role in Palmitate-Induced β-Cell Dysfunction In Vitro and In Vivo in Male Mice

The intracellular nucleotide-binding oligomerization domain (Nod) receptors of innate immunity have been demonstrated to play a significant role in metabolism. Saturated fatty acids have been reported to directly activate Nods, and deletion of Nod1 protects against glucose intolerance induced by a high-fat diet. This suggests a role for Nod1 in β-cells because glucose tolerance is heavily determined by β-cell performance. Therefore, we hypothesized that saturated fatty acid–induced β-cell dysfunction is mediated in part by Nod1 in the β-cell. Both mouse and human islets express Nod1 mRNA. Treatment with the Nod1 ligands C12 iE-DAP and FK565 decreased β-cell function in vitro and in vivo, respectively, in male mice. Mechanistically, this was mediated by JNK and IKKβ activation, because islets from JNK1-knockout (KO) and β-cell–specific IKKβ-KO mice were protected against Nod1 ligand–induced dysfunction. In vitro, islets of Nod1-KO mice were protected from palmitate-induced β-cell dysfunction. Similarly, in vivo, whole-body or β-cell–specific Nod1-KO mice were protected from palmitate-induced β-cell dysfunction during hyperglycemic clamps. Together, these data demonstrate that Nod1 plays a causal role in saturated fatty acid–induced β-cell dysfunction in vitro and in vivo in male mice. Article Highlights The innate immunity receptor nucleotide-binding oligomerization domain 1 (Nod1) can be activated by saturated fatty acids and is implicated in high-fat diet-induced inflammation and insulin resistance. This implies Nod1 plays a role in glucose homeostasis; therefore, we sought to determine whether saturated fatty acids cause pancreatic β-cell dysfunction through Nod1. Our data demonstrate that Nod1 is involved in palmitate-induced β-cell dysfunction in vitro and in vivo.