Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

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dc.contributor.authorCarrer, Micheleen
dc.contributor.authorLiu, Ningen
dc.contributor.authorGrueter, Chad E.en
dc.contributor.authorWilliams, Andrew H.en
dc.contributor.authorFrisard, Madlyn I.en
dc.contributor.authorHulver, Matthew W.en
dc.contributor.authorBassel-Duby, Rhondaen
dc.contributor.authorOlson, Eric N.en
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.date.accessioned2017-10-12T15:12:51Zen
dc.date.available2017-10-12T15:12:51Zen
dc.date.issued2012-09-18en
dc.description.abstractObesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mitochondrial biogenesis through stimulation of nuclear hormone receptors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitineO-acetyltransferase, a mitochondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex that controls nuclear hormone receptor activity, are repressed by miR-378 and miR-378*, respectively, and are elevated in the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the overall oxidative capacity of insulin target tissues. Thus, these miRNAs provide potential targets for pharmacologic intervention in obesity and metabolic syndrome.en
dc.description.sponsorshipWork in the laboratory of Eric Olson was supported by grants from the National Institutes of Health, Robert A. Welch Foundation (Grant I-0025), American Heart Association, Jon Holden DeHaan Foundation, Donald W. Reynolds Center for Clinical Cardiovascular Research, Fondation Leducq TransAtlantic Network of Excellence in Cardiovascular Research Program, and Cancer Prevention and Research Institute of Texas.en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1073/pnas.1207605109en
dc.identifier.issue38en
dc.identifier.urihttp://hdl.handle.net/10919/79622en
dc.identifier.volume109en
dc.language.isoenen
dc.publisherNASen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectfatty acid oxidationen
dc.subjectadipocytesen
dc.subjectmitochondrial CO₂ productionen
dc.titleControl of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*en
dc.title.serialPNASen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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