PPARγ-dependent remodeling of translational machinery in adipose progenitors is impaired in obesity

Mirian Krystel De Siqueira; Gaoyan Li; Yutian Zhao; Siqi Wang; In Sook Ahn; Mikayla Tamboline; Andrew D Hildreth; Jakeline Larios; Alejandro Schcolnik-Cabrera; Zaynab Nouhi; Zhengyi Zhang; Marcus J Tol; Vijaya Pandey; Shili Xu; Timothy E O'Sullivan; Julia J Mack; Peter Tontonoz; Tamer Sallam; James A Wohlschlegel; Laura Hulea; Xinshu Xiao; Xia Yang; Claudio J Villanueva

doi:10.1016/j.celrep.2024.114945

PPARγ-dependent remodeling of translational machinery in adipose progenitors is impaired in obesity

Cell Rep. 2024 Nov 7:114945. doi: 10.1016/j.celrep.2024.114945. Online ahead of print.

Authors

Mirian Krystel De Siqueira¹, Gaoyan Li¹, Yutian Zhao¹, Siqi Wang², In Sook Ahn¹, Mikayla Tamboline³, Andrew D Hildreth⁴, Jakeline Larios¹, Alejandro Schcolnik-Cabrera⁵, Zaynab Nouhi⁶, Zhengyi Zhang⁷, Marcus J Tol⁸, Vijaya Pandey⁹, Shili Xu¹⁰, Timothy E O'Sullivan⁴, Julia J Mack⁷, Peter Tontonoz⁸, Tamer Sallam⁷, James A Wohlschlegel⁹, Laura Hulea¹¹, Xinshu Xiao¹², Xia Yang¹³, Claudio J Villanueva¹⁴

Affiliations

¹ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.
³ Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA 90025, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90025, USA.
⁴ Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC H1T 2M4, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
⁶ Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC H1T 2M4, Canada.
⁷ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, Division of Cardiology, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA 90025, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90025, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90025, USA.
¹¹ Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC H1T 2M4, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada; Département de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
¹² Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90025, USA.
¹³ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90025, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁴ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: cvillanueva@ucla.edu.

PMID: 39579770
DOI: 10.1016/j.celrep.2024.114945

Abstract

Adipose tissue regulates energy homeostasis and metabolic function, but its adaptability is impaired in obesity. In this study, we investigate the impact of acute PPARγ agonist treatment in obese mice and find significant transcriptional remodeling of cells in the stromal vascular fraction (SVF). Using single-cell RNA sequencing, we profile the SVF of inguinal and epididymal adipose tissue of obese mice following rosiglitazone treatment and find an induction of ribosomal factors in both progenitor and preadipocyte populations, while expression of ribosomal factors is reduced with obesity. Notably, the expression of a subset of ribosomal factors is directly regulated by PPARγ. Polysome profiling of the epididymal SVF shows that rosiglitazone promotes translational selectivity of mRNAs that encode pathways involved in adipogenesis and lipid metabolism. Inhibition of translation using a eukaryotic translation initiation factor 4A (eIF4A) inhibitor is sufficient in blocking adipogenesis. Our findings shed light on how PPARγ agonists promote adipose tissue plasticity in obesity.

Keywords: CP: Metabolism; adipocytes; adipose progenitors; adipose stem cells; diabetes; glucose; obesity; ribosomes; rosiglitazone; translation.