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

Das, S.; Varshney, R.; Farriester, J. W.; Kyere-Davies, G.; Martinez, A. E.; Hill, K.; Kinter, M.; Mullen, G. P.; Nagareddy, P. R.; Rudolph, M. C.

doi:10.1101/2024.09.09.611047

bioRxiv · 10.1101/2024.09.09.611047

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

Das, S.·Varshney, R.·Farriester, J. W.·Kyere-Davies, G.·Martinez, A. E.·Hill, K.·Kinter, M.·Mullen, G. P.·Nagareddy, P. R.·Rudolph, M. C.

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Abstract

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 PPAR{gamma}, PGC1, 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 13C-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 PPAR{gamma}-PGC1 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.

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Das, S., Varshney, R., Farriester, J. W., Kyere-Davies, G., Martinez, A. E., Hill, K., Kinter, M., Mullen, G. P., Nagareddy, P. R., Rudolph, M. C.. 2024-09-09. NR2F2 Reactivation in Early-life Adipocyte Stem-like Cells Rescues Adipocyte Mitochondrial Oxidation. https://doi.org/10.1101/2024.09.09.611047

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