title: Hypothalamic miR-103 protects from hyperphagic obesity in mice.
abstract: The role of neuronal noncoding RNAs in energy control of the body is not fully understood. The arcuate nucleus (ARC) of the hypothalamus comprises neurons regulating food intake and body weight. Here we show that Dicer-dependent loss of microRNAs in these neurons of adult (DicerCKO) mice causes chronic overactivation of the signaling pathways involving phosphatidylinositol-3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) and an imbalance in the levels of neuropeptides, resulting in severe hyperphagic obesity. Similarly, the activation of PI3K-Akt-mTOR pathway due to Pten deletion in the adult forebrain leads to comparable weight increase. Conversely, the mTORC1 inhibitor rapamycin normalizes obesity in mice with an inactivated Dicer1 or Pten gene. Importantly, the continuous delivery of oligonucleotides mimicking microRNAs, which are predicted to target PI3K-Akt-mTOR pathway components, to the hypothalamus attenuates adiposity in DicerCKO mice. Furthermore, loss of miR-103 causes strong upregulation of the PI3K-Akt-mTOR pathway in vitro and its application into the ARC of the Dicer-deficient mice both reverses upregulation of Pik3cg, the mRNA encoding the catalytic subunit p110γ of the PI3K complex, and attenuates the hyperphagic obesity. Our data demonstrate in vivo the crucial role of neuronal microRNAs in the control of energy homeostasis.
authors.affiliation: Molecular Biology of the Cell I, ilya.vinnikov@gmail.com valery.grinevich@mpimf-heidelberg.mpg.de w.konopka@nencki.gov.pl.
authors.forename: Ilya A
authors.identifier: http://orcid.org/0000-0003-0488-8484
authors.initials: IA
authors.lastname: Vinnikov
authors.affiliation: Laboratory of Animal Models, Neurobiology Center, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Hajdukiewicz
authors.affiliation: ViroQuant-CellNetworks RNAi Screening Facility, BioQuant and.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Reymann
authors.affiliation: ViroQuant-CellNetworks RNAi Screening Facility, BioQuant and.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Beneke
authors.affiliation: Laboratory of Animal Models, Neurobiology Center, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Rafal
authors.initials: R
authors.lastname: Czajkowski
authors.affiliation: Schaller Research Group on Neuropeptides, German Cancer Research Center, 69120 Heidelberg, Germany, CellNetworks Cluster of Excellence, Department of Molecular Neurobiology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany.
authors.forename: Lena C
authors.initials: LC
authors.lastname: Roth
authors.affiliation: Molecular Biology of the Cell I.
authors.forename: Martin
authors.initials: M
authors.lastname: Novak
authors.affiliation: Institute for Bioinformatics and Systems Biology, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany, and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Roller
authors.affiliation: Molecular Biology of the Cell I.
authors.forename: Nicole
authors.initials: N
authors.lastname: Dörner
authors.affiliation: ViroQuant Screening of Cellular Networks, BioQuant, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Vytaute
authors.initials: V
authors.lastname: Starkuviene
authors.affiliation: Institute for Bioinformatics and Systems Biology, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany, and Department of Mathematics, Technical University Munich, 85748 Garching, Germany.
authors.forename: Fabian J
authors.identifier: http://orcid.org/0000-0002-2419-1943
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: ViroQuant-CellNetworks RNAi Screening Facility, BioQuant and.
authors.forename: Holger
authors.initials: H
authors.lastname: Erfle
authors.affiliation: Molecular Biology of the Cell I.
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.affiliation: Schaller Research Group on Neuropeptides, German Cancer Research Center, 69120 Heidelberg, Germany, CellNetworks Cluster of Excellence, Department of Molecular Neurobiology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany, ilya.vinnikov@gmail.com valery.grinevich@mpimf-heidelberg.mpg.de w.konopka@nencki.gov.pl.
authors.forename: Valery
authors.initials: V
authors.lastname: Grinevich
authors.affiliation: Molecular Biology of the Cell I, Laboratory of Animal Models, Neurobiology Center, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 02-093 Warsaw, Poland, ilya.vinnikov@gmail.com valery.grinevich@mpimf-heidelberg.mpg.de w.konopka@nencki.gov.pl.
authors.forename: Witold
authors.initials: W
authors.lastname: Konopka
mesh_terms: D015502:Absorptiometry, Photon; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D006963:Hyperphagia / Q000150:complications*; D007031:Hypothalamus / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000209:etiology* / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D054369:Agouti-Related Protein; D053487:DEAD-box RNA Helicases; D008164:Luminescent Proteins; D035683:MicroRNAs; D009478:Neuropeptide Y; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D043244:Ribonuclease III; D058570:TOR Serine-Threonine Kinases; C515199:Agrp protein, mouse; C555364:MIRN103 microRNA, mouse; C546843:mTOR protein, mouse; C509781:Dicer1 protein, mouse; C487757:Pten protein, mouse
keywords: Dicer; hypothalamus; metabolism; mice; microRNA; obesity
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