Dataset Information

MicroRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis.

ABSTRACT: In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)-379/410 genomic cluster as a key component of GC/GR-driven metabolic dysfunction. Particularly, miR-379 was up-regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR-dependent manner. Hepatocyte-specific silencing of miR-379 substantially reduced circulating very-low-density lipoprotein (VLDL)-associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR-379 effects on key receptors in hepatic TG re-uptake. As hepatic miR-379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR-controlled miRNA cluster not only defines a novel layer of hormone-dependent metabolic control but also paves the way to alternative miRNA-based therapeutic approaches in metabolic dysfunction.

SUBMITTER: de Guia RM

PROVIDER: S-EPMC4339121 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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microRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis.

de Guia Roldan M RM Rose Adam J AJ Sommerfeld Anke A Seibert Oksana O Strzoda Daniela D Zota Annika A Feuchter Yvonne Y Krones-Herzig Anja A Sijmonsma Tjeerd T Kirilov Milen M Sticht Carsten C Gretz Norbert N Dallinga-Thie Geesje G Diederichs Sven S Klöting Nora N Blüher Matthias M Berriel Diaz Mauricio M Herzig Stephan S

The EMBO journal 20141215 3

In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)-379/410 genomic cluster as a ...[more]

PMID: 25510864

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Project description:We often expect that investigations of the patterns, causes, and consequences of among-individual variation in a trait of interest will reveal how selective pressures or ecological conditions influence that trait. However, many endocrine traits, such as concentrations of glucocorticoid (GC) hormones, exhibit adaptive plasticity and, therefore, do not necessarily respond to these pressures as predicted by among-individual phenotypic correlations. To improve our interpretations of among-individual variation in GC concentrations, we need more information about the repeatability of these traits within individuals. Many studies have already estimated the repeatability of baseline, stress-induced, and integrated GC measures, which provides an opportunity to use meta-analytic techniques to investigate (1) whether GC titers are generally repeatable across taxa, and (2) which biological or methodological factors may impact these estimates. From an intensive search of the literature, we collected 91 GC repeatability estimates from 47 studies. Overall, we found evidence that GC levels are repeatable, with mean repeatability estimates across studies ranging from 0.230 for baseline levels to 0.386 for stress-induced levels. We also noted several factors that predicted the magnitude of these estimates, including taxon, sampling season, and lab technique. Amphibians had significantly higher repeatability in baseline and stress-induced GCs than birds, mammals, reptiles, or bony fish. The repeatability of stress-induced GCs was higher when measured within, rather than across, life history stages. Finally, estimates of repeatability in stress-induced and integrated GC measures tended to be lower when GC concentrations were quantified using commercial kit assays rather than in-house assays. The extent to which among-individual variation in GCs may explain variation in organismal performance or fitness (and thereby inform our understanding of the ecological and evolutionary processes driving that variation) depends on whether measures of GC titers accurately reflect how individuals differ overall. Our findings suggest that while GC titers can reflect some degree of consistent differences among individuals, they frequently may not. We discuss how our findings contribute to interpretations of variation in GCs, and suggest routes for the design and analysis of future research.

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MicroRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis.

Publications

microRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis.

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