title: The microRNA-29 Family Dictates the Balance Between Homeostatic and Pathological Glucose Handling in Diabetes and Obesity.
abstract: The microRNA-29 (miR-29) family is among the most abundantly expressed microRNA in the pancreas and liver. Here, we investigated the function of miR-29 in glucose regulation using miR-29a/b-1 (miR-29a)-deficient mice and newly generated miR-29b-2/c (miR-29c)-deficient mice. We observed multiple independent functions of the miR-29 family, which can be segregated into a hierarchical physiologic regulation of glucose handling. miR-29a, and not miR-29c, was observed to be a positive regulator of insulin secretion in vivo, with dysregulation of the exocytotic machinery sensitizing β-cells to overt diabetes after unfolded protein stress. By contrast, in the liver both miR-29a and miR-29c were important negative regulators of insulin signaling via phosphatidylinositol 3-kinase regulation. Global or hepatic insufficiency of miR-29 potently inhibited obesity and prevented the onset of diet-induced insulin resistance. These results demonstrate strong regulatory functions for the miR-29 family in obesity and diabetes, culminating in a hierarchical and dose-dependent effect on premature lethality.
authors.affiliation: VIB, Leuven, Belgium Department of Microbiology and Immunology, KUL - University of Leuven, Leuven, Belgium james.dooley@vib-kuleuven.be adrian.liston@vib.be.
authors.forename: James
authors.initials: J
authors.lastname: Dooley
authors.affiliation: VIB, Leuven, Belgium Department of Microbiology and Immunology, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Josselyn E
authors.initials: JE
authors.lastname: Garcia-Perez
authors.affiliation: VIB, Leuven, Belgium Department of Microbiology and Immunology, KUL - University of Leuven, Leuven, Belgium Department of Oncology, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Jayasree
authors.initials: J
authors.lastname: Sreenivasan
authors.affiliation: VIB, Leuven, Belgium Department of Microbiology and Immunology, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Schlenner
authors.affiliation: Department of Clinical and Experimental Medicine, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Roman
authors.initials: R
authors.lastname: Vangoitsenhoven
authors.affiliation: VIB, Leuven, Belgium Center for Human Genetics, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Aikaterini S
authors.initials: AS
authors.lastname: Papadopoulou
authors.affiliation: VIB, Leuven, Belgium Department of Microbiology and Immunology, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Lei
authors.initials: L
authors.lastname: Tian
authors.affiliation: VIB, Leuven, Belgium Department of Microbiology and Immunology, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Susann
authors.initials: S
authors.lastname: Schonefeldt
authors.affiliation: VIB, Leuven, Belgium Center for Human Genetics, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Serneels
authors.affiliation: Department of Imaging and Pathology, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Deroose
authors.affiliation: VIB, Leuven, Belgium Department of Microbiology and Immunology, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Staats
authors.affiliation: Department of Clinical and Experimental Medicine, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Van der Schueren
authors.affiliation: VIB, Leuven, Belgium Center for Human Genetics, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Owen P
authors.initials: OP
authors.lastname: McGuinness
authors.affiliation: Department of Clinical and Experimental Medicine, KUL - University of Leuven, Leuven, Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.affiliation: VIB, Leuven, Belgium Department of Microbiology and Immunology, KUL - University of Leuven, Leuven, Belgium james.dooley@vib-kuleuven.be adrian.liston@vib.be.
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005089:Exocytosis; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases