NR2F2 Reactivation in Early-life Adipocyte Stem-like Cells Rescues Adipocyte Mitochondrial Oxidation.

Autor:	Das S; Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA., Varshney R; Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA., Farriester JW; Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA., Kyere-Davies G; Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA., Martinez AE; Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA., Hill K; Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA., Kinter M; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK., Mullen GP; Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA., Nagareddy PR; Deptartment of Internal Medicine, Cardiovascular Section, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA., Rudolph MC; Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 09. Date of Electronic Publication: 2024 Sep 09.
DOI:	10.1101/2024.09.09.611047
Abstrakt:	In humans, perinatal exposure to an elevated omega-6 (n6) relative to omega-3 (n3) Fatty Acid (FA) ratio is associated with the likelihood of childhood obesity. In mice, we show perinatal exposure to excessive n6-FA programs neonatal Adipocyte Stem-like cells (ASCs) to differentiate into adipocytes with lower mitochondrial nutrient oxidation and a propensity for nutrient storage. Omega-6 FA exposure reduced fatty acid oxidation (FAO) capacity, coinciding with impaired induction of beige adipocyte regulatory factors PPARγ, PGC1α, PRDM16, and UCP1. ASCs from n6-FA exposed pups formed adipocytes with increased lipogenic genes in vitro, consistent with an in vivo accelerated adipocyte hypertrophy, greater triacylglyceride accumulation, and increased % body fat. Conversely, n6-FA exposed pups had impaired whole animal 13 C-palmitate oxidation. The metabolic nuclear receptor, NR2F2, was suppressed in ASCs by excess n6-FA intake preceding adipogenesis. ASC deletion of NR2F2, prior to adipogenesis, mimicked the reduced FAO capacity observed in ASCs from n6-FA exposed pups, suggesting that NR2F2 is required in ASCs for robust beige regulator expression and downstream nutrient oxidation in adipocytes. Transiently re-activating NR2F2 with ligand prior to differentiation in ASCs from n6-FA exposed pups, restored their FAO capacity as adipocytes by increasing the PPARγ-PGC1α axis, mitochondrial FA transporter CPT1A, ATP5 family synthases, and NDUF family Complex I proteins. Our findings suggest that excessive n6-FA exposure early in life dampens an NR2F2-mediated induction of beige adipocyte regulators, resulting in metabolic programming that is shifted towards nutrient storage. Competing Interests: Competing Interests The authors declare no competing interests.
Databáze:	MEDLINE
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