title: Weight Loss Upregulates the Small GTPase DIRAS3 in Human White Adipose Progenitor Cells, Which Negatively Regulates Adipogenesis and Activates Autophagy via Akt-mTOR Inhibition.
abstract: Long-term weight-loss (WL) interventions reduce insulin serum levels, protect from obesity, and postpone age-associated diseases. The impact of long-term WL on adipose-derived stromal/progenitor cells (ASCs) is unknown. We identified DIRAS3 and IGF-1 as long-term WL target genes up-regulated in ASCs in subcutaneous white adipose tissue of formerly obese donors (WLDs). We show that DIRAS3 negatively regulates Akt, mTOR and ERK1/2 signaling in ASCs undergoing adipogenesis and acts as a negative regulator of this pathway and an activator of autophagy. Studying the IGF-1-DIRAS3 interaction in ASCs of WLDs, we demonstrate that IGF-1, although strongly up-regulated in these cells, hardly activates Akt, while ERK1/2 and S6K1 phosphorylation is activated by IGF-1. Overexpression of DIRAS3 in WLD ASCs completely inhibits Akt phosphorylation also in the presence of IGF-1. Phosphorylation of ERK1/2 and S6K1 is lesser reduced under these conditions. In conclusion, our key findings are that DIRAS3 down-regulates Akt-mTOR signaling in ASCs of WLDs. Moreover, DIRAS3 inhibits adipogenesis and activates autophagy in these cells.
authors.affiliation: Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Asim
authors.initials: A
authors.lastname: Ejaz
authors.affiliation: Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Mitterberger
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Plastic and Reconstructive Surgery, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Mattesich
authors.affiliation: Department of Anatomy, Histology and Embryology, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Marit E
authors.initials: ME
authors.lastname: Zwierzina
authors.affiliation: Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hörl
authors.affiliation: Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kaiser
authors.affiliation: Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Viertler
authors.affiliation: Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Rostek
authors.affiliation: Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meryk
authors.affiliation: Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Sana
authors.initials: S
authors.lastname: Khalid
authors.affiliation: Department of Plastic and Reconstructive Surgery, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Pierer
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bast
authors.affiliation: Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria. Electronic address: werner.zwerschke@uibk.ac.at.
authors.forename: Werner
authors.initials: W
authors.lastname: Zwerschke
mesh_terms: D050156:Adipogenesis; D000328:Adult; D000818:Animals; D001343:Autophagy; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D050151:Subcutaneous Fat / Q000166:cytology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015431:Weight Loss; D055815:Young Adult; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C117386:DIRAS3 protein, human; C583557:IGF1 protein, human; D007334:Insulin-Like Growth Factor I; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020741:rho GTP-Binding Proteins
keywords: Adipogenesis; Aging; Akt; Autophagy; Caloric restriction; DIRAS3; ERK1/2; Human adipose-derived stromal/progenitor cells; IGF-1; Insulin; Obesity; Weight loss; mTOR