The major cap-binding protein eIF4E regulates lipid homeostasis and diet-induced obesity

Crystal S. Conn, Haojun Yang, Harrison J. Tom, Kenji Ikeda, Juan A. Oses-Prieto, Hieu Vu, Yasuo Oguri, Supna Nair, Ryan M. Gill, Shingo Kajimura, Ralph J. DeBerardinis, Alma L. Burlingame, Davide Ruggero

Research output: Contribution to journalArticlepeer-review

Abstract

Obesity is a global epidemic leading to increased mortality and susceptibility to comorbidities, with few viable therapeutic interventions. A hallmark of disease progression is the ectopic deposition of lipids in the form of lipid droplets in vital organs such as the liver. However, the mechanisms underlying the dynamic storage and processing of lipids in peripheral organs remain an outstanding question. Here, we show an unexpected function for the major cap-binding protein, eIF4E, in high-fat-diet-induced obesity. In response to lipid overload, select networks of proteins involved in fat deposition are altered in eIF4E-deficient mice. Specifically, distinct messenger RNAs involved in lipid metabolic processing and storage pathways are enhanced at the translation level by eIF4E. Failure to translationally upregulate these mRNAs results in increased fatty acid oxidation, which enhances energy expenditure. We further show that inhibition of eIF4E phosphorylation genetically—and by a potent clinical compound—restrains weight gain following intake of a high-fat diet. Together, our study uncovers translational control of lipid processing as a driver of high-fat-diet-induced weight gain and provides a pharmacological target to treat obesity.

Original languageEnglish (US)
Pages (from-to)244-257
Number of pages14
JournalNature Metabolism
Volume3
Issue number2
DOIs
StatePublished - Feb 2021

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Internal Medicine
  • Cell Biology
  • Medicine(all)

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