Disruption of nucleotide biosynthesis reprograms mitochondrial metabolism to inhibit adipogenesis
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.
Authors
- Antentor Hinton (ORCID: https://orcid.org/0000-0002-7730-952X)
- Jacob W. Myers (ORCID: https://orcid.org/0000-0002-0288-2161)
- Woo Yong Park (ORCID: https://orcid.org/0000-0003-4188-3826)
- Ryoichi Bessho (ORCID: https://orcid.org/0009-0009-2682-6947)
- Jean‐Philippe Cartailler (ORCID: https://orcid.org/0000-0002-0312-2391)
- Alex M. Eddie
- Matthew A. Cottam (ORCID: https://orcid.org/0000-0003-0619-1605)
- Elizabeth R. Nunn
- Elma Zaganjor (ORCID: https://orcid.org/0000-0003-0600-7417)
- Jessica B. Spinelli (ORCID: https://orcid.org/0000-0003-3657-4578)
- Julia A. Pinette (ORCID: https://orcid.org/0000-0003-0715-7708)
- Volker H. Haase (ORCID: https://orcid.org/0000-0002-7051-8994)
- Zer Vue (ORCID: https://orcid.org/0000-0002-3502-8906)
- Claudia Montufar
- Zayedali Shaikh
- Genesis A Wilson
- Heather Bryant (ORCID: https://orcid.org/0009-0008-3086-6266)
Institutions
- University of Massachusetts Chan Medical School (US)
- Vanderbilt University (US)
- VA Tennessee Valley Healthcare System (US)
- Vanderbilt Health (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Journal of Lipid Research
- Published
- 2024-09-06
- DOI
- https://doi.org/10.1016/j.jlr.2024.100641
- Citations
- 4
- Primary Topic
- Peroxisome Proliferator-Activated Receptors
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- American Heart Association
- American Society of Nephrology
- Vanderbilt University
- National Institutes of Health
- School of Medicine, Vanderbilt University
- Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center
- Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center
- National Institute of General Medical Sciences