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

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.

• Authors: Michele Carrer, Ning Liu, Chad E Grueter, Andrew H Williams, Madlyn I Frisard, Matthew W Hulver, Rhonda Bassel-Duby, Eric N Olson
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 38 Pg. 15330-5 (Sep 18 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22949648 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids
• MIRN378 microRNA, mouse
• MicroRNAs
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• Trans-Activators
• Transcription Factors
• Carbon Dioxide

Topics

• Adipocytes (cytology)
• Animals
• Carbon Dioxide (chemistry)
• Crosses, Genetic
• Energy Metabolism
• Fatty Acids (chemistry)
• Female
• Gene Deletion
• Homeostasis
• Male
• Metabolic Syndrome (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• Mitochondria (metabolism)
• Models, Biological
• Models, Genetic
• Obesity (metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Recombination, Genetic
• Signal Transduction
• Trans-Activators (metabolism)
• Transcription Factors
• Transcriptional Activation