Neonatal intake of Omega-3 fatty acids enhances lipid oxidation in adipocyte precursors

Rohan Varshney; Snehasis Das; G Devon Trahan; Jacob W Farriester; Gregory P Mullen; Gertrude Kyere-Davies; David M Presby; Julie A Houck; Patricia G Webb; Monika Dzieciatkowska; Kenneth L Jones; Matthew S Rodeheffer; Jacob E Friedman; Paul S MacLean; Michael C Rudolph

doi:10.1016/j.isci.2022.105750

Neonatal intake of Omega-3 fatty acids enhances lipid oxidation in adipocyte precursors

iScience. 2022 Dec 6;26(1):105750. doi: 10.1016/j.isci.2022.105750. eCollection 2023 Jan 20.

Authors

Affiliations

¹ Harold Hamm Diabetes Center and Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
² Department of Pediatrics, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA.
³ Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, CO, USA.
⁴ Department of Reproductive Science, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, CO, USA.
⁵ Department of Biochemistry & Molecular Genetics, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, CO, USA.
⁶ Department of Cell Biology and Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁷ Department of Molecular, Cellular and Developmental Biology, Department of Comparative Medicine, Yale University, New Haven, CT, USA.

Abstract

Establishing metabolic programming begins during fetal and postnatal development, and early-life lipid exposures play a critical role during neonatal adipogenesis. We define how neonatal consumption of a low omega-6 to -3 fatty acid ratio (n6/n3 FA ratio) establishes FA oxidation in adipocyte precursor cells (APCs) before they become adipocytes. In vivo, APCs isolated from mouse pups exposed to the low n6/n3 FA ratio had superior FA oxidation capacity, elevated beige adipocyte mRNAs Ppargc1α, Ucp2, and Runx1, and increased nuclear receptor NR2F2 protein. In vitro, APC treatment with NR2F2 ligand-induced beige adipocyte mRNAs and increased mitochondrial potential but not mass. Single-cell RNA-sequencing analysis revealed low n6/n3 FA ratio yielded more mitochondrial-high APCs and linked APC NR2F2 levels with beige adipocyte signatures and FA oxidation. Establishing beige adipogenesis is of clinical relevance, because fat depots with energetically active, smaller, and more numerous adipocytes improve metabolism and delay metabolic dysfunction.

Keywords: Biological sciences; Endocrine regulation; Endocrinology.