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Postprandial regulation of hepatic microRNAs predicted to target the insulin pathway in rainbow trout.

Mennigen JA, Panserat S, Larquier M, Plagnes-Juan E, Medale F, Seiliez I, Skiba-Cassy S - PLoS ONE (2012)

Bottom Line: A concurrent increase in the activity of the hepatic insulin signaling pathway and the expression of lipogenic genes (srebp1c, fas, acly) was equally observed, while lipolytic gene expression (cpt1a and cpt1b) decreased significantly 4 h after the meal.This suggests lipogenic roles of omy-miRNA-33 and omy-miRNA-122b may be conserved between rainbow trout and mammals and that these miRNAs may furthermore contribute to acute postprandial regulation of de novo hepatic lipid synthesis in rainbow trout.These findings provide a framework for future research of miRNA regulation of hepatic metabolism in trout and will help to further elucidate the metabolic phenotype of rainbow trout.

View Article: PubMed Central - PubMed

Affiliation: UMR1067 Nutrition, Métabolisme, Aquaculture, Institut National de la Recherche Agronomique, Saint-Pée-sur-Nivelle, Pyrénées-Atlantiques, France.

ABSTRACT
Rainbow trout are carnivorous fish and poor metabolizers of carbohydrates, which established this species as a model organism to study the comparative physiology of insulin. Following the recent characterisation of key roles of several miRNAs in the insulin action on hepatic intermediary metabolism in mammalian models, we investigated the hypothesis that hepatic miRNA expression is postprandially regulated in the rainbow trout and temporally coordinated in the context of insulin-mediated regulation of metabolic gene expression in the liver. To address this hypothesis, we used a time-course experiment in which rainbow trout were fed a commercial diet after short-term fasting. We investigated hepatic miRNA expression, activation of the insulin pathway, and insulin regulated metabolic target genes at several time points. Several miRNAs which negatively regulate hepatic insulin signaling in mammalian model organisms were transiently increased 4 h after the meal, consistent with a potential role in acute postprandial negative feed-back regulation of the insulin pathway and attenuation of gluconeogenic gene expression. We equally observed a transient increase in omy- miRNA-33 and omy-miRNA-122b 4 h after feeding, whose homologues have potent lipogenic roles in the liver of mammalian model systems. A concurrent increase in the activity of the hepatic insulin signaling pathway and the expression of lipogenic genes (srebp1c, fas, acly) was equally observed, while lipolytic gene expression (cpt1a and cpt1b) decreased significantly 4 h after the meal. This suggests lipogenic roles of omy-miRNA-33 and omy-miRNA-122b may be conserved between rainbow trout and mammals and that these miRNAs may furthermore contribute to acute postprandial regulation of de novo hepatic lipid synthesis in rainbow trout. These findings provide a framework for future research of miRNA regulation of hepatic metabolism in trout and will help to further elucidate the metabolic phenotype of rainbow trout.

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Schematic representation of experimentally validated actions of mammalian miRNAs on the mammalian hepatic insulin signaling pathway.Encircled + or – symbols indicate a stimulatory and inhibitory role on the insulin pathway in mammalian model systems. See text for explanations.
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pone-0038604-g001: Schematic representation of experimentally validated actions of mammalian miRNAs on the mammalian hepatic insulin signaling pathway.Encircled + or – symbols indicate a stimulatory and inhibitory role on the insulin pathway in mammalian model systems. See text for explanations.

Mentions: In recent mammalian literature [5], [6], [7], an involvement of miRNAs in the aetiology of insulin resistance in type-II diabetes has been hypothesized through the identification of altered hepatic expression of miRNAs in animal models of obesity and insulin-resistance. miRNAs are a family of short transcribed non-coding nucleotide sequences (∼21 nt), which are exported from the nucleus to bind to the mRNAs of target genes by complementary base-pairing mediated by the seed region of the miRNA [8]. The binding between miRNA and its specific mRNA target(s) results in the formation of a RISC (RNA-induced silencing complex), which, depending on the amount of complementarity of base pairing, causes degradation of the target mRNA or inhibition of its translation, respectively [8]. The identification of particular miRNAs as potential regulators of hepatic metabolism in mammals was followed by the demonstration of direct physiological functions of these individual mammalian miRNAs on components of the hepatic insulin pathway, which can be divided into several nodes [9], as depicted in Fig. 1. Briefly, insulin acts to recruit IRS proteins (node 1), which in turn recruit PI3K (node 2) to phosphorylate Akt (node 3). Downstream of Akt, the insulin pathway is bifurcated [10], and subsequent metabolic effects are to a large extent mediated by mTOR and FoxO1. The mTOR pathway subsequently regulates S6K1 and 4-EBP1 to stimulate hepatic protein synthesis and, at least partially, is involved in the stimulation of lipogenesis by stimulating SREBP1C-dependent gene expression [10], [11]. The FoxO1 pathway is primarily known to mediate insulin dependent repression of hepatic gluconeogenesis, at the level of gene expression [12]. Both, phosphorylation of mTOR and FoxO1 have been shown to inhibit hepatic autophagy [13], [14], and thereby further contribute to systemic amino acid, glucose [15], and lipid [16] homeostasis in mammals.


Postprandial regulation of hepatic microRNAs predicted to target the insulin pathway in rainbow trout.

Mennigen JA, Panserat S, Larquier M, Plagnes-Juan E, Medale F, Seiliez I, Skiba-Cassy S - PLoS ONE (2012)

Schematic representation of experimentally validated actions of mammalian miRNAs on the mammalian hepatic insulin signaling pathway.Encircled + or – symbols indicate a stimulatory and inhibitory role on the insulin pathway in mammalian model systems. See text for explanations.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368902&req=5

pone-0038604-g001: Schematic representation of experimentally validated actions of mammalian miRNAs on the mammalian hepatic insulin signaling pathway.Encircled + or – symbols indicate a stimulatory and inhibitory role on the insulin pathway in mammalian model systems. See text for explanations.
Mentions: In recent mammalian literature [5], [6], [7], an involvement of miRNAs in the aetiology of insulin resistance in type-II diabetes has been hypothesized through the identification of altered hepatic expression of miRNAs in animal models of obesity and insulin-resistance. miRNAs are a family of short transcribed non-coding nucleotide sequences (∼21 nt), which are exported from the nucleus to bind to the mRNAs of target genes by complementary base-pairing mediated by the seed region of the miRNA [8]. The binding between miRNA and its specific mRNA target(s) results in the formation of a RISC (RNA-induced silencing complex), which, depending on the amount of complementarity of base pairing, causes degradation of the target mRNA or inhibition of its translation, respectively [8]. The identification of particular miRNAs as potential regulators of hepatic metabolism in mammals was followed by the demonstration of direct physiological functions of these individual mammalian miRNAs on components of the hepatic insulin pathway, which can be divided into several nodes [9], as depicted in Fig. 1. Briefly, insulin acts to recruit IRS proteins (node 1), which in turn recruit PI3K (node 2) to phosphorylate Akt (node 3). Downstream of Akt, the insulin pathway is bifurcated [10], and subsequent metabolic effects are to a large extent mediated by mTOR and FoxO1. The mTOR pathway subsequently regulates S6K1 and 4-EBP1 to stimulate hepatic protein synthesis and, at least partially, is involved in the stimulation of lipogenesis by stimulating SREBP1C-dependent gene expression [10], [11]. The FoxO1 pathway is primarily known to mediate insulin dependent repression of hepatic gluconeogenesis, at the level of gene expression [12]. Both, phosphorylation of mTOR and FoxO1 have been shown to inhibit hepatic autophagy [13], [14], and thereby further contribute to systemic amino acid, glucose [15], and lipid [16] homeostasis in mammals.

Bottom Line: A concurrent increase in the activity of the hepatic insulin signaling pathway and the expression of lipogenic genes (srebp1c, fas, acly) was equally observed, while lipolytic gene expression (cpt1a and cpt1b) decreased significantly 4 h after the meal.This suggests lipogenic roles of omy-miRNA-33 and omy-miRNA-122b may be conserved between rainbow trout and mammals and that these miRNAs may furthermore contribute to acute postprandial regulation of de novo hepatic lipid synthesis in rainbow trout.These findings provide a framework for future research of miRNA regulation of hepatic metabolism in trout and will help to further elucidate the metabolic phenotype of rainbow trout.

View Article: PubMed Central - PubMed

Affiliation: UMR1067 Nutrition, Métabolisme, Aquaculture, Institut National de la Recherche Agronomique, Saint-Pée-sur-Nivelle, Pyrénées-Atlantiques, France.

ABSTRACT
Rainbow trout are carnivorous fish and poor metabolizers of carbohydrates, which established this species as a model organism to study the comparative physiology of insulin. Following the recent characterisation of key roles of several miRNAs in the insulin action on hepatic intermediary metabolism in mammalian models, we investigated the hypothesis that hepatic miRNA expression is postprandially regulated in the rainbow trout and temporally coordinated in the context of insulin-mediated regulation of metabolic gene expression in the liver. To address this hypothesis, we used a time-course experiment in which rainbow trout were fed a commercial diet after short-term fasting. We investigated hepatic miRNA expression, activation of the insulin pathway, and insulin regulated metabolic target genes at several time points. Several miRNAs which negatively regulate hepatic insulin signaling in mammalian model organisms were transiently increased 4 h after the meal, consistent with a potential role in acute postprandial negative feed-back regulation of the insulin pathway and attenuation of gluconeogenic gene expression. We equally observed a transient increase in omy- miRNA-33 and omy-miRNA-122b 4 h after feeding, whose homologues have potent lipogenic roles in the liver of mammalian model systems. A concurrent increase in the activity of the hepatic insulin signaling pathway and the expression of lipogenic genes (srebp1c, fas, acly) was equally observed, while lipolytic gene expression (cpt1a and cpt1b) decreased significantly 4 h after the meal. This suggests lipogenic roles of omy-miRNA-33 and omy-miRNA-122b may be conserved between rainbow trout and mammals and that these miRNAs may furthermore contribute to acute postprandial regulation of de novo hepatic lipid synthesis in rainbow trout. These findings provide a framework for future research of miRNA regulation of hepatic metabolism in trout and will help to further elucidate the metabolic phenotype of rainbow trout.

Show MeSH