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Disruption of nucleotide biosynthesis reprograms mitochondrial metabolism to inhibit adipogenesis.

Authors :
Pinette JA
Myers JW
Park WY
Bryant HG
Eddie AM
Wilson GA
Montufar C
Shaikh Z
Vue Z
Nunn ER
Bessho R
Cottam MA
Haase VH
Hinton AO
Spinelli JB
Cartailler JP
Zaganjor E
Source :
Journal of lipid research [J Lipid Res] 2024 Oct; Vol. 65 (10), pp. 100641. Date of Electronic Publication: 2024 Sep 06.
Publication Year :
2024

Abstract

A key organismal response to overnutrition involves the development of new adipocytes through the process of adipogenesis. Preadipocytes sense changes in the systemic nutrient status and metabolites can directly modulate adipogenesis. We previously identified a role of de novo nucleotide biosynthesis in adipogenesis induction, whereby inhibition of nucleotide biosynthesis suppresses the expression of the transcriptional regulators PPARγ and C/EBPα. Here, we set out to identify the global transcriptomic changes associated with the inhibition of nucleotide biosynthesis. Through RNA sequencing (RNAseq), we discovered that mitochondrial signatures were the most altered in response to inhibition of nucleotide biosynthesis. Blocking nucleotide biosynthesis induced rounded mitochondrial morphology, and altered mitochondrial function, and metabolism, reducing levels of tricarboxylic acid cycle intermediates, and increasing fatty acid oxidation (FAO). The loss of mitochondrial function induced by suppression of nucleotide biosynthesis was rescued by exogenous expression of PPARγ. Moreover, inhibition of FAO restored PPARγ expression, mitochondrial protein expression, and adipogenesis in the presence of nucleotide biosynthesis inhibition, suggesting a regulatory role of nutrient oxidation in differentiation. Collectively, our studies shed light on the link between substrate oxidation and transcription in cell fate determination.<br />Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1539-7262
Volume :
65
Issue :
10
Database :
MEDLINE
Journal :
Journal of lipid research
Publication Type :
Academic Journal
Accession number :
39245323
Full Text :
https://doi.org/10.1016/j.jlr.2024.100641