Journal article
Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378
Proceedings of the National Academy of Sciences - PNAS, Vol.109(38), pp.15330-15335
09/18/2012
DOI: 10.1073/pnas.1207605109
PMCID: PMC3458360
PMID: 22949648
Abstract
Obesity 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, carnitine O-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.
Details
- Title: Subtitle
- Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378
- Creators
- Michele Carrer - Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USANing LiuChad E GrueterAndrew H WilliamsMadlyn I FrisardMatthew W HulverRhonda Bassel-DubyEric N Olson
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.109(38), pp.15330-15335
- DOI
- 10.1073/pnas.1207605109
- PMID
- 22949648
- PMCID
- PMC3458360
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- R01 HL077439 / NHLBI NIH HHS R01 HL111665 / NHLBI NIH HHS R01 HL093039 / NHLBI NIH HHS
- Language
- English
- Date published
- 09/18/2012
- Academic Unit
- Cardiovascular Medicine; Craniofacial Anomalies Research Center; Internal Medicine
- Record Identifier
- 9984094621902771
Metrics
17 Record Views