Deoxyhypusine synthase promotes a pro-inflammatory macrophage phenotype.

The metabolic inflammation (meta-inflammation) of obesity is characterized by proinflammatory macrophage infiltration into adipose tissue. Catalysis by deoxyhypusine synthase (DHPS) modifies the translation factor eIF5A to generate a hypusine (Hyp) residue. Hypusinated eIF5A (eIF5A^Hyp) controls the translation of mRNAs involved in inflammation, but its role in meta-inflammation has not been elucidated. Levels of eIF5A^Hyp were found to be increased in adipose tissue macrophages from obese mice and in murine macrophages activated to a proinflammatory M1-like state. Global proteomics and transcriptomics revealed that DHPS deficiency in macrophages altered the abundance of proteins involved in NF-κB signaling, likely through translational control of their respective mRNAs. DHPS deficiency in myeloid cells of obese mice suppressed M1 macrophage accumulation in adipose tissue and improved glucose tolerance. 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. [Display omitted] • eIF5A^Hyp is enriched in adipose tissue macrophages in obesity • Proinflammatory macrophages augment DHPS and eIF5A^Hyp production • DHPS supports the production of proteins that promote NFκB signaling in macrophages • Dhps deletion in macrophages of obese mice improves insulin sensitivity and glycemia Anderson-Baucum et al. show that eIF5A hypusination, catalyzed by deoxyhypusine synthase (DHPS), is a feature of macrophages that reside in adipose tissue of obese mice. The authors show that deletion of the Dhps gene in macrophages blunts their proinflammatory characteristics, resulting in improved insulin sensitivity and glucose homeostasis. [ABSTRACT FROM AUTHOR]