bioRxiv - Physiology最新文献

{"title":"Nanomedicines targeting signaling of protease-activated receptor 2 in organelles provide sustained analgesia","authors":"Shavonne L. Teng, Rocco Latorre, Divya Bhansali, Parker K. Lewis, Rachel E. Pollard, Chloe J. Peach, Badr Sokrat, Gokul S.A. Thanigai, Tracy Chiu, Dane D. Jensen, Nestor N. Jimenez-Vargas, Abby Mocherniak, Lucas T. Parreiras-E-Silva, Michel Bouvier, Matthew Bogyo, Michael M. Gaspari, Stephen J. Vanner, Nathalie M. Pinkerton, Kam W. Leong, Brian L. Schmidt, Nigel W. Bunnett","doi":"10.1101/2024.09.10.612022","DOIUrl":"https://doi.org/10.1101/2024.09.10.612022","url":null,"abstract":"Although many internalized G protein-coupled receptors (GPCRs) continue to signal, the mechanisms and outcomes of GPCR signaling in organelles are uncertain due to the challenges of measuring organelle-specific signals and of selectively antagonizing receptors in intracellular compartments. Herein, genetically-encoded biosensors targeted to subcellular compartments were used to analyze organelle-specific signaling of protease-activated receptor 2 (PAR₂); the propensity of nanoparticles (NPs) to accumulate in endosomes was leveraged to selectively antagonize intracellular PAR₂ signaling of pain. PAR₂ agonists evoked sustained activation of PAR2, Gαq and β-arrestin-1 in early, late and recycling endosomes and the <em>cis</em>- and <em>trans</em>. Golgi apparatus, and activated extracellular signal regulated kinase (ERK) in the cytosol and nucleus, measured with organelle-targeted biosensors. Dendrimer and core-shell polymeric NPs accumulated in early and late endosomes of HEK293 cells, colonic epithelial cells and nociceptors, detected by confocal imaging of fluorescent NPs. NPs efficiently encapsulated and slowly released AZ3451, a negative allosteric PAR2 antagonist. NP-encapsulated AZ3451, but not unencapsulated AZ3451, rapidly and completely reversed PAR₂, Gαq and β-arrestin-1 activation in endosomes and the Golgi apparatus and ERK activation in the cytosol and nucleus. When administered into the mouse colon lumen, dendrimer NPs accumulated in endosomes of colonocytes and polymeric NPs targeted neurons, sites of PAR₂ expression. Both NP-AZ3451 formulations, but not unencapsulated AZ3451, caused long-lasting analgesia and normalized aberrant behavior in preclinical models of inflammatory bowel disease. Thus, organelle-specific PAR₂ signals in colonocytes and nociceptors mediate pain. Antagonism of PAR₂ in organelles, rather than at the plasma membrane, provides effective pain relief.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute sildenafil administration reduces susceptibility to induced atrial fibrillation in sheep","authors":"Nathan denham, George WP Madders, David Hutchings, Charlotte ER Smith, Alice Whitley, Mohammed Obeidat, Andrew Trafford, Charles Pearman, Katharine Dibb","doi":"10.1101/2024.09.09.612118","DOIUrl":"https://doi.org/10.1101/2024.09.09.612118","url":null,"abstract":"Background: Sildenafil is a PDE5 inhibitor with a very good safety profile and animal models suggest it may be beneficial in the treatment of heart failure and ventricular fibrillation. Sildenafil has also been associated with a reduced incidence of atrial fibrillation (AF) in a retrospective observational study. We have therefore sought to determine whether sildenafil has a direct effect on atrial electrophysiology and resultant AF burden. Methods: Invasive electrophysiological studies were performed in 12 anaesthetised healthy adult female Welsh mountain sheep. Pacing protocols were performed in the right atrium before and after administration of an acute 10 mg intravenous bolus of sildenafil and the burden of AF assessed. Results: Sildenafil profoundly reduced the vulnerability to AF, decreasing AF duration (112.2 +/- 73.5 s vs. 3.3 +/- 1.4 s), the number of burst pacing inductions causing AF (90 % vs 70 %) and the complexity of AF. The antiarrhythmic effects of sildenafil were determined to be resultant of prolongation of both the atrial effective refractory period (146.9 +/- 7.2 ms vs 166.2 +/- 32.5 ms) and the atrial excitation wavelength (12.9 +/- 0.07 cm vs 15.0 +/- 0.07 cm) and resulted in a shallower restitution curve, reflected in a decreased magnitude of monophasic action potential alternans (0.09 +/- 0.001 mV vs 0.05 +/- 0.10 mV). Conclusions: In the subjectively healthy atria of a highly translational model a strong antiarrhythmic effect upon acute sildenafil application was observed suggestive of a potential clinical benefit in AF.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"119 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"G3BP1 Maintains Vascular Endothelial Barrier Integrity by Negatively Regulating the MYD88-ARNO-ARF6 Signaling Pathway","authors":"Bin Wen, Weiyue Sun, Haoran Wu, Yuxi He, Huiqiao Chen, Yuanhui Meng, Guofang Tang, Jinshun Zhu, Zhengwang Wen, Rongzhou Wu, Guowei Wu, Chunxiang Zhang, Maoping Chu","doi":"10.1101/2024.09.09.612151","DOIUrl":"https://doi.org/10.1101/2024.09.09.612151","url":null,"abstract":"Objective: We investigated the role of the RNA-binding protein G3BP1 in regulating endothelial permeability. Approach and Results: We examined the effects of loss of G3bp1 in conditional knockout mice and primary human HUVEC cells. We analyzed endothelial barrier integrity and permeability, focusing on AJ and TJ expression, under both normal and LPS-induced inflammatory conditions. Loss of G3bp1 in vascular endothelial cells decreased AJ and TJ expression, compromised barrier integrity, and increased permeability. These effects were exacerbated under LPS-induced inflammatory conditions. Loss of g3bp1 also increased the expression of MYD88, ARNO, and ARF6, and enhanced ARF6 activity. Mechanistically, G3BP1 bound to and stabilized MYD88 mRNA, negatively regulating the MYD88-ARNO-ARF6 signaling pathway. Inhibiting this pathway by reducing MYD88 or ARF6 expression, or inhibiting ARNO activity, restored AJ/TJ expression and barrier function in G3BP1-deficient models. Conclusion: Our findings identify G3BP1 as a novel regulator of vascular endothelial permeability. G3BP1 acts by negatively regulating the MYD88-ARNO-ARF6 signaling pathway.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"99 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging-associated vacuolation of multi-ciliated cells in the distal mouse oviduct reflects unique cell identity and luminal microenvironment","authors":"Keerthana Harwalkar, Nobuko Yamanaka, Alain S Pacis, Selina Zhao, Katie Teng, Warwick Pitman, Mitaali Taskar, Vera Lynn, Alex Frances Thornton, Matthew J Ford, Yojiro Yamanaka","doi":"10.1101/2024.09.07.611808","DOIUrl":"https://doi.org/10.1101/2024.09.07.611808","url":null,"abstract":"The female reproductive organs present with the earliest aging characteristics, such as a decline in fertility and estrous cyclicity. While age-related changes in the ovary are well-documented, it is unclear if any age-associated changes occur in the other female reproductive organs, such as the oviduct/fallopian tube. The recent recognition of the distal end of the fallopian tube as the tissue of origin of high-grade serous tubal ovarian carcinomas (HGSCs), and that its patient demographic is strongly biased to postmenopausal women, motivated us to investigate age-associated changes in this organ. At the distal end of aged oviducts in mice, we found vacuolated multi-ciliated cells (MCCs) with a severely apically displaced and deformed nucleus. This phenotype was unique to the distal oviduct epithelium - infundibulum (INF) and ampulla (AMP). Ovariectomy did not affect the timeline of MCC vacuolation, suggesting little involvement of ovulation and hormonal regulation. MCC vacuolation was induced in hypoxia or hydroxyurea treatments in in vitro organotypic culture of all oviduct regions, not limited to the INF/AMP epithelium. This suggests high oxygen demand in MCCs, compared to other cell types, and a uniquely stressed INF/AMP epithelial microenvironment in vivo. We found that the blood circulation of INF/AMP depended on the ovarian artery, different from the rest of the oviduct epithelium and its circulation declined along with ovarian activities. We conclude that a decline in local blood circulation and distinct cellular identity of the INF/AMP epithelium caused age-associated MCC vacuolation, reflecting its mild, chronically stressed microenvironment.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatic GCGR is required for the superior weight loss effects of a structurally related analogue of the dual GCGR/GLP1R agonist survodutide","authors":"Fen Long, Manuel Klug, Tenagne D. Challa, Vissarion Efthymiou, Christian Wolfrum, Carla Horvath","doi":"10.1101/2024.09.09.611134","DOIUrl":"https://doi.org/10.1101/2024.09.09.611134","url":null,"abstract":"The dual glucagon/glucagon-like peptide 1 receptor (GCGR/GLP1R) agonists have superior efficacy in promoting weight loss and metabolic improvements in obesity and metabolic dysfunction-associated steatohepatitis (MASH) than current available mono-agonists. However, the mechanisms underlying these benefits are not fully understood. While the effects on appetite regulation and glucose control through GLP1R agonism are well established, the role of GCGR agonism in promoting weight loss and metabolic changes is less defined. Using a dual GCGR/GLP1R agonist BI 456908 and a selective GLP1R agonist semaglutide, we could show that the dual agonist achieved superior weight loss efficacy by engaging hepatic GCGR without adversely affecting glucose control. Furthermore, we could demonstrate that hepatic GCGR is critical for facilitating plasma and liver lipid clearance stimulated by the dual agonist. Overall, these findings highlight the crucial metabolic contributions of hepatic GCGR to the efficacy of combined GCGR/GL1R activation.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TMPRSS6 cleaves KCNE1 and causes arrhythmias in iron overload disease","authors":"Stefan Peischard, Philipp Kastl, Gunnar Goerges, Julian A. Schreiber, Arie O Verkerk, Ronald Wilders, Paul Disse, Isabelle Hornung, Ursula Klingmüller, Andrea Steinbicker, Martina Rauner, Maya Vujic, Frank Rosenbauer, Sven Meuth, Thomas Budde, Per A. Pedersen, Thomas A. Jepps, Thomas Jespersen, Nathalie Strutz-Seebohm, Guiscard Seebohm","doi":"10.1101/2024.09.04.611322","DOIUrl":"https://doi.org/10.1101/2024.09.04.611322","url":null,"abstract":"Iron storage disease is associated with cardiovascular manifestations, including various forms of cardiac arrhythmias of unknown origin. In this study, cardiac arrhythmias associated with iron overload were investigated in human iPSC-derived cardiomyocytes (hiPSC-CM) and hiPSC-derived sinus node-like pacemaker cells. Among other effects, iron overload leads to an increase in the plasma membrane-anchored protease TMPRSS6. TMPRSS6 cleaves the auxiliary subunit KCNE1 N-terminally and thus modulates the function of both the IKs (KCNQ1/KCNE1 current) and the If (HCN4/KCNE1) ion channels. Furthermore, TMPRSS6 induces a reduction of electric field potential (EFP) count and increased duration in hiPSC-derived ventricular-like cells and in hiPSC-derived pacemaker-like cells. In accordance with these in vitro generated results, TMPRSS6-mediated interactions show pro-arrhythmic effects in silico. Therefore, the TMPRSS6 - KCNE1-KCNQ1 and TMPRSS6 - KCNE1-HCN4 cascades may represent new clinically relevant pro-arrhythmic mechanisms in iron overload diseases.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysyl Oxidases are Necessary for Myometrial Contractility and On-Time Parturition in Mice","authors":"Alexis Ouellette, Christina Do, Sydney Cohn-Guthrie, Ying-Wai Lam, Mala Mahendroo, Shanmugasundaram Nallasamy","doi":"10.1101/2024.09.05.610344","DOIUrl":"https://doi.org/10.1101/2024.09.05.610344","url":null,"abstract":"The extracellular matrix (ECM) plays a pivotal role in the maintenance of tissue mechanical homeostasis. Collagens and elastic fibers are the most predominant fibrous ECM proteins providing tissue mechanical function through covalent cross-linking which is mediated by the lysyl oxidase family of enzymes. In this study, the function of lysyl oxidases in maintaining the integrity of the extracellular matrix in the myometrium and its impact on parturition-timing was investigated. Gene and protein expression analyses demonstrate that a sub-set of the lysyl oxidase family of enzymes are highly induced in pregnant myometrium. Inhibition of the activity of the lysyl oxidase family of enzymes through β-aminopropionitrile (BAPN) delays parturition in mice, in part, due to myometrial dysfunction. In BAPN treated mice, the expression of genes encoding contraction associated proteins such as connexin 43, oxytocin receptor and prostaglandin synthase 2 is significantly reduced in the myometrium compared to the untreated control mice. Proteomic analysis revealed that the composition of the ECM is altered in response to BAPN treatment which demonstrates that the inhibition of the activity of lysyl oxidases disrupted the integrity of the myometrial ECM. Our findings demonstrate that the lysyl oxidases-mediated ECM function is necessary for the myometrium to transition from the quiescent to contractile phenotype at term for on-time parturition.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"71 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Left Atrial Strain as a Predictor of Cardiac Dysfunction in a Murine Model of Pressure Overload","authors":"John P Salvas, Thomas Moore-Morris, Craig J Goergen, Pierre Sicard","doi":"10.1101/2024.09.05.611376","DOIUrl":"https://doi.org/10.1101/2024.09.05.611376","url":null,"abstract":"Aim: Left atrial (LA) strain is emerging as a valuable metric for evaluating cardiac function, particularly under pathological conditions such as pressure overload. This preclinical study investigates the predictive utility of LA strain on cardiac function in a murine model subjected to pressure overload, mimicking pathologies such as hypertension and aortic stenosis. Methods: High resolution ultrasound was performed in a cohort of mice (n=16) to evaluate left atrial and left ventricular function at baseline and 2- and 4-weeks after transverse aortic constriction (TAC). Acute adaptations in cardiac function were assessed in a subgroup of mice (n=10) with 3-days post TAC imaging. Results: We report an increase in LA max volume from 11.0 plus-or-minus sign 4.3lower case Greek muL at baseline to 26.7 plus-or-minus sign 16.7lower case Greek muL at 4 weeks (p=0.002) and a decrease in LA strain from 19.6 plus-or-minus sign 4.8% at baseline to 10.1 plus-or-minus sign 6.3% at 4 weeks (p=0.006). In the acute phase, LA strain dysfunction was present at 3-days (p&lt;0.001) prior to alterations in LA volume (p=0.856) or left ventricular (LV) ejection fraction (p=0.120). LA strain correlated with key indicators of cardiac performance including left ventricular (LV) ejection fraction (r=0.563, p&lt;0.001), longitudinal strain (r=-0.643, p&lt;0.001) and strain rate (r=0.387, p=0.007). Furthermore, markers of atrial structure and function including LA max volume (AUC=0.858, p&lt;0.001), ejection fraction (AUC=0.901 p&lt;0.001), and strain (AUC=0.878, p&lt;0.001) all predicted LV dysfunction. Conclusion: LA strain and function assessments provide a reliable, non-invasive method for early detection and prediction of cardiac dysfunction in a model of pressure overload.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipocyte-specific deletion of Dbc1 does not recapitulate healthy obesity phenotype but suggests regulation of inflammation signaling","authors":"Leonardo Santos, Rafael Sebastian Fort, Geraldine Schlapp, Karina Cal, Valentina Perez-Torrado, Maria Noel Meikle, Ana Paula Mulet, Jose Sotelo-Silveira, Jose M Verdes, Paola Contreras, Aldo J Calliari, Jose L Badano, Martina Crispo, Carlos Escande","doi":"10.1101/2024.09.08.611743","DOIUrl":"https://doi.org/10.1101/2024.09.08.611743","url":null,"abstract":"The protein Deleted in Breast Cancer 1 (DBC1), a regulator of several transcription factors and epigenetic modulators, plays determinant roles in metabolism regulation, obesity and aging- related processes. Knockout mice for DBC1, develop morbid obesity but are protected against liver steatosis, insulin resistance and atherosclerosis. We have proposed that this healthy obesity phenotype was mainly due to the expansion of adipose tissue, avoiding free-fatty acid spillover and metabolic damage in peripheral tissues. To gain more insight about the role of Dbc1 in adipose cells during obesity and its impact on metabolic dysregulation, we generated a conditional DBC1 KO mouse and backcrossed it with CRE-AdipoQ transgenic mice, aiming to abrogate Dbc1 expression in all mature adipocytes (cAT-DBC1). cAT-Dbc1 mice showed deletion of Dbc1 specifically in mature adipocytes in different fat depots. We tested the effect of Dbc1 deletion in adipocytes on different aspects of metabolic regulation in male and female mice fed in normal chow and high-fat diets. We found that deletion of DBC1 in mature adipocytes had no effect on weight gain, glucose tolerance and other markers of metabolic dysregulation, regardless sex. However, Dbc1 KO adipocytes displayed an mRNA expression profile consistent with increased inflammation during obesity. Our results suggest that the healthy phenotype displayed in the whole body Dbc1 KO obese mice is not due to the protein function in mature adipocytes and might involve other cell types present in adipose tissue. Instead, the specific deletion of DBC1 in mature adipocytes highlights a novel role of Dbc1 in inflammation signaling during obesity.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NR2F2 Reactivation in Early-life Adipocyte Stem-like Cells Rescues Adipocyte Mitochondrial Oxidation","authors":"Snehasis Das, Rohan Varshney, Jacob W Farriester, Gertrude Kyere-Davies, Alexandrea E Martinez, Kaitlyn Hill, Michael Kinter, Gregory P Mullen, Prabhakara R Nagareddy, Michael C Rudolph","doi":"10.1101/2024.09.09.611047","DOIUrl":"https://doi.org/10.1101/2024.09.09.611047","url":null,"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 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 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 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.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"207 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}