Gema Frühbeck1, Blanca Fernández-Quintana2, Mirla Paniagua2, Ana Wenting Hernández-Pardos2, Víctor Valentí3, Rafael Moncada4, Victoria Catalán5, Sara Becerril5, Javier Gómez-Ambrosi5, Piero Portincasa6, Camilo Silva7, Javier Salvador7, Amaia Rodríguez8. 1. Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008, Pamplona, Spain. 2. Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008, Pamplona, Spain. 3. CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Surgery, Clínica Universidad de Navarra, 31008, Pamplona, Spain. 4. CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Anesthesia, Clínica Universidad de Navarra, 31008, Pamplona, Spain. 5. Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. 6. Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology University of Bari Medical School, Policlinico Hospital, Bari, Italy. 7. CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008, Pamplona, Spain. 8. Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. Electronic address: arodmur@unav.es.
Abstract
BACKGROUND: Fibronectin type IIIdomain-containing protein 4 (FNDC4) constitutes a secreted factor showing a high homology in the fibronectin type III and transmembrane domains with the exercise-associated myokine irisin (FNDC5). We sought to evaluate whether FNDC4 mimics the anti-obesity effects of FNDC5/irisin in human adipose tissue. METHODS: Plasma and adipose tissue samples of 78 patients with morbid obesity undergoing bariatric surgery and 26 normal-weight individuals were used in the present study. RESULTS: Plasma FNDC4 was decreased in patients with morbid obesity, related to obesity-associated systemic inflammation and remained unchanged six months after bariatric surgery. Visceral adipose tissue from patients with morbid obesity showed higher expression of FNDC4 and its putative receptor GPR116 regardless of the degree of insulin resistance. FNDC4 content was regulated by lipogenic, lipolytic and proinflammatory stimuli in human visceral adipocytes. FNDC4 reduced intracytosolic lipid accumulation and stimulated a brown-like pattern in human adipocytes, as evidenced by an upregulated expression of UCP-1 and the brown/beige adipocyte markers PRDM16, TMEM26 and CD137. Moreover, FNDC4 treatment upregulated mitochondrial DNA content and factors involved in mitochondrial biogenesis (TFAM, NRF1 and NRF2). Human FNDC4-knockdown adipocytes exhibited an increase in lipogenesis and a reduction of brown/beige-specific fat markers as well as factors involved in mitochondrial biogenesis. CONCLUSIONS: Taken together, the novel adipokine FNDC4 reduces lipogenesis and increases fat browning in human visceral adipocytes. The upregulation of FNDC4 in human visceral fat might constitute an attempt to attenuate the adipocyte hypertrophy, inflammation and impaired beige adipogenesis in the obese state.
BACKGROUND: Fibronectin type IIIdomain-containing protein 4 (FNDC4) constitutes a secreted factor showing a high homology in the fibronectin type III and transmembrane domains with the exercise-associated myokine irisin (FNDC5). We sought to evaluate whether FNDC4 mimics the anti-obesity effects of FNDC5/irisin in human adipose tissue. METHODS: Plasma and adipose tissue samples of 78 patients with morbid obesity undergoing bariatric surgery and 26 normal-weight individuals were used in the present study. RESULTS: Plasma FNDC4 was decreased in patients with morbid obesity, related to obesity-associated systemic inflammation and remained unchanged six months after bariatric surgery. Visceral adipose tissue from patients with morbid obesity showed higher expression of FNDC4 and its putative receptor GPR116 regardless of the degree of insulin resistance. FNDC4 content was regulated by lipogenic, lipolytic and proinflammatory stimuli in human visceral adipocytes. FNDC4 reduced intracytosolic lipid accumulation and stimulated a brown-like pattern in human adipocytes, as evidenced by an upregulated expression of UCP-1 and the brown/beige adipocyte markers PRDM16, TMEM26 and CD137. Moreover, FNDC4 treatment upregulated mitochondrial DNA content and factors involved in mitochondrial biogenesis (TFAM, NRF1 and NRF2). HumanFNDC4-knockdown adipocytes exhibited an increase in lipogenesis and a reduction of brown/beige-specific fat markers as well as factors involved in mitochondrial biogenesis. CONCLUSIONS: Taken together, the novel adipokine FNDC4 reduces lipogenesis and increases fat browning in human visceral adipocytes. The upregulation of FNDC4 in human visceral fat might constitute an attempt to attenuate the adipocyte hypertrophy, inflammation and impaired beige adipogenesis in the obese state.
Authors: Esther C Gallegos-Cabriales; Ernesto Rodriguez-Ayala; Hugo A Laviada-Molina; Edna J Nava-Gonzalez; Rocío A Salinas-Osornio; Lorena Orozco; Irene Leal-Berumen; Juan Carlos Castillo-Pineda; Laura Gonzalez-Lopez; Claudia Escudero-Lourdes; Judith Cornejo-Barrera; Fabiola Escalante-Araiza; Eira E Huerta-Avila; Fatima A Buenfil-Rello; Vanessa-Giselle Peschard; Eliud Silva; Rosa A Veloz-Garza; Angelica Martinez-Hernandez; Francisco M Barajas-Olmos; Fernanda Molina-Segui; Lucia Gonzalez-Ramirez; Ruy D Arjona-Villicaña; Victor M Hernandez-Escalante; Janeth F Gaytan-Saucedo; Zoila Vaquera; Monica Acebo-Martinez; Areli Murillo-Ramirez; Sara P Diaz-Tena; Benigno Figueroa-Nuñez; Melesio E Valencia-Rendon; Rafael Garzon-Zamora; Juan Manuel Viveros-Paredes; Salvador B Valdovinos-Chavez; Anthony G Comuzzie; Karin Haack; Ashley A Thorsell; Xianlin Han; Shelley A Cole; Raul A Bastarrachea Journal: Biology (Basel) Date: 2021-12-16