title: MicroRNA-155 Deficiency Leads to Decreased Atherosclerosis, Increased White Adipose Tissue Obesity, and Non-alcoholic Fatty Liver Disease: A NOVEL MOUSE MODEL OF OBESITY PARADOX.
abstract: Obesity paradox (OP) describes a widely observed clinical finding of improved cardiovascular fitness and survival in some overweight or obese patients. The molecular mechanisms underlying OP remain enigmatic partly due to a lack of animal models mirroring OP in patients. Using apolipoprotein E knock-out (apoE-/-) mice on a high fat (HF) diet as an atherosclerotic obesity model, we demonstrated 1) microRNA-155 (miRNA-155, miR-155) is significantly up-regulated in the aortas of apoE-/-mice, and miR-155 deficiency in apoE-/-mice inhibits atherosclerosis; 2) apoE-/-/miR-155-/-(double knock-out (DKO)) mice show HF diet-induced obesity, adipocyte hypertrophy, and present with non-alcoholic fatty liver disease; 3) DKO mice demonstrate HF diet-induced elevations of plasma leptin, resistin, fed-state and fasting insulin and increased expression of adipogenic transcription factors but lack glucose intolerance and insulin resistance. Our results are the first to present an OP model using DKO mice with features of decreased atherosclerosis, increased obesity, and non-alcoholic fatty liver disease. Our findings suggest the mechanistic role of reduced miR-155 expression in OP and present a new OP working model based on a single miRNA deficiency in diet-induced obese atherogenic mice. Furthermore, our results serve as a breakthrough in understanding the potential mechanism underlying OP and provide a new biomarker and novel therapeutic target for OP-related metabolic diseases.
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Anthony
authors.initials: A
authors.lastname: Virtue
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Candice
authors.initials: C
authors.lastname: Johnson
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Jahaira
authors.initials: J
authors.lastname: Lopez-Pastraña
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shao
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Hangfei
authors.initials: H
authors.lastname: Fu
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Ya-Feng
authors.initials: YF
authors.lastname: Li
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yin
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Jietang
authors.initials: J
authors.lastname: Mai
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Victor
authors.initials: V
authors.lastname: Rizzo
authors.affiliation: the Monell Chemical Senses Center, Philadelphia, Pennsylvania 19104, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Tordoff
authors.affiliation: the Vascular Biology Center, Augusta University, Augusta, Georgia 30912.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bagi
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Huimin
authors.initials: H
authors.lastname: Shan
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140, xfyang@temple.edu.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yang
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D004041:Dietary Fats; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse
keywords: atherosclerosis; inflammation; liver; microRNA (miRNA); obesity