title: Targeting FoxO1 with AS1842856 suppresses adipogenesis.
abstract: Hyperplasia (i.e., increased adipogenesis) contributes to excess adiposity, the hallmark of obesity that can trigger metabolic complications. As FoxO1 has been implicated in adipogenic regulation, we investigated the kinetics of FoxO1 activation during adipocyte differentiation, and tested the effects of FoxO1 antagonist (AS1842856) on adipogenesis. We found for the first time that the kinetics of FoxO1 activation follows a series of sigmoid curves, and reveals the phases relevant to clonal expansion, cell cycle arrest, and the regulation of PPARγ, adiponectin, and mitochondrial proteins (complexes I and III). In addition, multiple activation-inactivation transitions exist in the stage of terminal differentiation. Importantly, persistent inhibition of FoxO1 with AS1842856 almost completely suppressed adipocyte differentiation, while selective inhibition in specific stages had differential effects on adipogenesis. Our data present a new view of FoxO1 in adipogenic regulation, and suggest AS1842856 can be an anti-obesity agent that warrants further investigation.
authors.affiliation: a Department of Human Nutrition, Foods and Exercise; Fralin Life Science Institute; College of Agriculture and Life Science; Virginia Tech , Blacksburg , VA USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.forename: Longhua
authors.initials: L
authors.lastname: Liu
authors.forename: Louise
authors.initials: L
authors.lastname: Zheng
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Stoneman
authors.forename: Alicia
authors.initials: A
authors.lastname: Cho
authors.forename: Ashley
authors.initials: A
authors.lastname: Emery
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gilbert
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Cheng
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D015363:Quinolones / Q000008:administration & dosage*
chemical_list: C553926:5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D015363:Quinolones
keywords: AS1842856; AS1842856, 5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid; BMI, basal media I; BMII, basal media II; C1, mitochondrial complex I; C3, mitochondrial complex III; DMI, differentiation media I; DMII, differentiation media II; FoxO1; FoxO1, forkhead box O1; G6P, glucose 6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; PPARγ, peroxisome proliferator-activated receptor gamma; T2DM, type 2 diabetes mellitus; adipogenesis; mitochondria; obesity