(P31-052-23) The Role of FoxO1 in Adipose Transdifferentiation and Iron Metabolism

Objectives: Adipocyte transdifferentiation plays an important role in adipose plasticity and metabolic homeostasis. The molecular mechanism of transdifferentiation remains incompletely understood.

Methods: RNA sequencing and qPCR were used to profile gene expression during adipose transdifferentiation. Western blotting, histological assays, and high resolution respirometry were used to analyze signaling transduction pathways and cellular functions. Indirect calorimetry was employed to analyze energy expenditure.

Results: We found that the transcription factor forkhead Box O1 (FoxO1) regulates adipose transdifferentiation by mediating transforming growth factor-β1 (Tgfβ1) signaling pathway. Tgfβ1 treatment induced whitening phenotype in beige adipocytes, reducing UCP1 and mitochondrial capacity but enlarging lipid droplets. Deletion of adipose FoxO1 (adO1KO) dampened Tgfβ1 signaling by downregulating Tgfbr2 and Smad3 and induced browning of adipose tissue in mice, increasing UCP1 and mitochondrial content and activating metabolic pathways. Silencing FoxO1 also abolished the whitening effect of Tgfβ1 on beige adipocytes. The adO1KO mice exhibited a significantly higher energy expenditure, lower fat mass, and smaller adipocytes than the control mice. The browning phenotype in adO1KO mice was associated with an increased iron content in adipose tissue, concurrent with upregulation of proteins that facilitate iron uptake (DMT1 and TfR1) and iron import into mitochondria (Mfrn1). Analysis of hepatic and serum iron along with hepatic iron-regulatory proteins (ferritin and ferroportin) in the adO1KO mice revealed an adipose tissue-liver crosstalk that meets the increased iron requirement for adipose browning. The FoxO1-Tgfβ1 signaling cascade also underlay adipose browning induced by β3-AR agonist CL316243.

Conclusions: Our study provides the first evidence of FoxO1-Tgfβ1 axis in the regulation of adipose browning-whitening transdifferentiation and iron influx, which sheds light on the compromised adipose plasticity in conditions of dysregulated FoxO1 and Tgfβ1 signaling.

Funding Sources: American Heart Association, USDA National Institute of Food and Agriculture