eIF5AHyp is enriched in adipose tissue macrophages in obesity
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Proinflammatory macrophages augment DHPS and eIF5AHyp production
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DHPS supports the production of proteins that promote NFκB signaling in macrophages
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Dhps deletion in macrophages of obese mice improves insulin sensitivity and glycemia
Summary
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 (eIF5AHyp) controls the translation of mRNAs involved in inflammation, but its role in meta-inflammation has not been elucidated. Levels of eIF5AHyp 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.
RNA sequencing data have been deposited in GEO and all proteomics data have been deposited in Proteome Exchange and all are publicly available as of the date of publication. Accession numbers are listed in the key resources table. All primary data presented in this paper have been deposited as a unified Prism 9.1.1 file at Mendeley and are publicly available as of the date of publication, and all original immunoblot images are provided in a single PowerPoint file at Mendeley and are also available as of the date of publication. The DOI is listed in the key resources table. Original microscopy data reported in this paper will be shared by the lead contact upon request.
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This paper does not report original code.
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Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
