FoxO1 regulates adipose transdifferentiation and iron influx by mediating Tgfβ1 signaling pathway
Limin Shi,
Zhipeng Tao,
Louise Zheng,
Jinying Yang,
Xinran Hu,
Karen Scott,
Annette de Kloet,
Eric Krause,
James F. Collins,
Zhiyong Cheng
Affiliations
Limin Shi
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, 32611, USA; Interdisciplinary Nutritional Sciences Doctoral Program, Center for Nutritional Sciences, University of Florida, Gainesville, FL, 32611, USA; Center for Integrative Cardiovascular and Metabolic Diseases, University of Florida, Gainesville, FL, 32610, USA
Zhipeng Tao
Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA, 24061, USA; Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA
Louise Zheng
Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA, 24061, USA
Jinying Yang
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, 32611, USA; Interdisciplinary Nutritional Sciences Doctoral Program, Center for Nutritional Sciences, University of Florida, Gainesville, FL, 32611, USA
Xinran Hu
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, 32611, USA
Karen Scott
Center for Integrative Cardiovascular and Metabolic Diseases, University of Florida, Gainesville, FL, 32610, USA; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL32610, USA
Annette de Kloet
Center for Integrative Cardiovascular and Metabolic Diseases, University of Florida, Gainesville, FL, 32610, USA; Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL, 32610, USA
Eric Krause
Center for Integrative Cardiovascular and Metabolic Diseases, University of Florida, Gainesville, FL, 32610, USA; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL32610, USA
James F. Collins
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, 32611, USA; Interdisciplinary Nutritional Sciences Doctoral Program, Center for Nutritional Sciences, University of Florida, Gainesville, FL, 32611, USA
Zhiyong Cheng
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, 32611, USA; Interdisciplinary Nutritional Sciences Doctoral Program, Center for Nutritional Sciences, University of Florida, Gainesville, FL, 32611, USA; Center for Integrative Cardiovascular and Metabolic Diseases, University of Florida, Gainesville, FL, 32610, USA; Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA, 24061, USA; Corresponding author. Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, 32611, USA.
Adipose plasticity is critical for metabolic homeostasis. Adipocyte transdifferentiation plays an important role in adipose plasticity, but the molecular mechanism of transdifferentiation remains incompletely understood. Here we show that the transcription factor FoxO1 regulates adipose transdifferentiation by mediating Tgfβ1 signaling pathway. Tgfβ1 treatment induced whitening phenotype in beige adipocytes, reducing UCP1 and mitochondrial capacity and 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. Our study provides the first evidence of a 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.
