title: Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5).
abstract: Reducing the expression of the Indy (I'm Not Dead Yet) gene in lower organisms extends life span by mechanisms resembling caloric restriction. Similarly, deletion of the mammalian homolog, mIndy (Slc13a5), encoding for a plasma membrane tricarboxylate transporter, protects from aging- and diet-induced adiposity and insulin resistance in mice. The organ specific contribution to this phenotype is unknown. We examined the impact of selective inducible hepatic knockdown of mIndy on whole body lipid and glucose metabolism using 2'-O-methoxyethyl chimeric anti-sense oligonucleotides (ASOs) in high-fat fed rats. 4-week treatment with 2'-O-methoxyethyl chimeric ASO reduced mIndy mRNA expression by 91% (P=0.001) compared to control ASO. Besides similar body weights between both groups, mIndy-ASO treatment lead to a 74% reduction in fasting plasma insulin concentrations as well as a 35% reduction in plasma triglycerides. Moreover, hepatic triglyceride content was significantly reduced by the knockdown of mIndy, likely mediating a trend to decreased basal rates of endogenous glucose production as well as an increased suppression of hepatic glucose production by 25% during a hyperinsulinemic-euglycemic clamp. Together, these data suggest that inducible liver-selective reduction of mIndy in rats is able to ameliorate hepatic steatosis and insulin resistance, conditions occurring with high calorie diets and during aging.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.|Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.|Department of Sport Science, Medical Section, University of Innsbruck, Innsbruck, Austria.|Department of Visceral, Transplant, and Thoracic Surgery, D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria.|Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany.
authors.forename: Dominik H
authors.initials: DH
authors.lastname: Pesta
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.|Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Perry
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Fitsum
authors.initials: F
authors.lastname: Guebre-Egziabher
authors.affiliation: Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Dongyan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Jurczak
authors.affiliation: Charité - University School of Medicine, Department of Endocrinology, Diabetes and Nutrition, Berlin, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Fischer-Rosinsky
authors.affiliation: Charité - University School of Medicine, Department of Endocrinology, Diabetes and Nutrition, Berlin, Germany.|Section of Metabolic Vascular Medicine, Medical Clinic III and Paul Langerhans Institute Dresden (PLID), TU Dresden, Germany.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Daniels
authors.affiliation: Section of Metabolic Vascular Medicine, Medical Clinic III and Paul Langerhans Institute Dresden (PLID), TU Dresden, Germany.|German Center for Diabetes Research (DZD), Dresden, Germany.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Willmes
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.affiliation: Section of Metabolic Vascular Medicine, Medical Clinic III and Paul Langerhans Institute Dresden (PLID), TU Dresden, Germany.|German Center for Diabetes Research (DZD), Dresden, Germany.|Section of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London, UK.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: University Clinic Erlangen, Erlangen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Knauf
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.|Veterans Affairs Medical Center, West Haven, CT, USA.
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.|Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: Section of Metabolic Vascular Medicine, Medical Clinic III and Paul Langerhans Institute Dresden (PLID), TU Dresden, Germany.|German Center for Diabetes Research (DZD), Dresden, Germany.|Section of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London, UK.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects*; D005234:Fatty Liver / Q000139:chemically induced*; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008136:Longevity / Q000235:genetics*; D016376:Oligonucleotides, Antisense; D051381:Rats; D027981:Symporters / Q000235:genetics / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D016376:Oligonucleotides, Antisense; C469354:Slc13a5 protein, rat; D027981:Symporters; D005947:Glucose
keywords: Indy; Slc13a5; aging; hepatic insulin resistance; type 2 diabetes