PNNL

Abstract

Obesity is characterized by adipose tissue expansion, macrophage infiltration, and the development of chronic low-grade meta-inflammation that drives insulin resistance and metabolic dysfunction. Eukaryotic translation initiation factor 5A (elF5A) is the only protein known to be uniquely post- translationally modified and activated by deoxyhypusine synthase (DHPS) to generate a hypusine (Hyp) residue. Activated elF5A (elF5AHyp) controls the translation of a subset of mRNAs that play a role in inflammation, but a role for the DHPS/elF5AHyp axis in obesity-associated adipose tissue inflammation has not been tested. We found DHPS/elF5AHyp levels to be increased in adipose tissue macrophages from mice fed a high fat diet and in murine macrophages activated to a proinflammatory M1-like state. Translation analysis by sucrose gradient sedimentation and RNA immunoprecipitation revealed that elF5AHyp binds to and controls the translation initiation of mRNAs encoding lL-1? and MlP-1a, factors expressed in M1 macrophages. Global proteomics and transcriptomics analysis revealed that DHPS deficiency in M1 macrophages altered the abundance of key inflammatory mediators involved in NF-KB signaling without changes in their mRNA levels, a finding consistent with a role for DHPS in translation of mRNAs. DHPS deficiency in myeloid cells of high fat-fed mice suppressed M1 macrophage accumulation in adipose tissue and improved glucose tolerance. Together, these findings indicate that DHPS promotes the post-transcriptional regulation of a subset of mRNAs governing inflammation and chemotaxis in macrophages and contributes to a proinflammatory M1-like phenotype.