Review
Meta-regulation: microRNA regulation of glucose and lipid metabolism

https://doi.org/10.1016/j.tem.2009.05.007Get rights and content

Maintenance of homeostasis during environmental flux requires constant metabolic adjustment, achieved partly through the fine regulation of gene expression. MicroRNAs are key players in this regulatory milieu; they have been implicated in regulating gene expression within several metabolically active tissues including the endocrine pancreas, liver and adipose tissue. Recent studies, for example, implicate miR-375 in pancreatic islet cell viability and function, and removal or overexpression of miR-375 profoundly affects glucose metabolism. In the liver, miR-122 is important for normal lipid metabolism. In fact, misexpression of miRNAs can occur in some diseases, suggesting that restoring miRNA expression is a potential therapeutic approach for both metabolic syndrome and diabetes.

Section snippets

miRNAs: an emerging player in the regulatory milieu

Gene expression can be controlled at the transcriptional level by the activity of DNA-binding transcription factors or controlled post-transcriptionally by changes in RNA stability or localization, protein translation or biological half-life. Since the description of the regulatory mechanisms active in the Escherichia coli operon, there has been great interest across phyla in cis regulatory-driven transcriptional control of gene expression through trans-acting protein factors. More recently, a

Transcription, processing and biological action of miRNAs

In humans, approximately 720 miRNA genes are scattered throughout the genome; 70% of these are located in regions void of protein-coding genes and 30% within introns of protein-coding transcripts. Some miRNAs are situated in independent transcriptional units; however, a great number are generated from either transcripts containing clusters of miRNAs or the intronic sequences of protein coding genes. Most miRNA transcription is carried out from regulated gene promoters by RNA polymerase II 1, 2.

Pancreatic islet miRNAs regulate glucose metabolism

During embryonic development, the pancreatic primordia bud from the posterior foregut endoderm and the endocrine, exocrine and ductal structures, and subsequently differentiate through a complex branching morphogenic process [15]. Disruption of Dicer1 and subsequent loss of miRNAs early in pancreatic organogenesis leads to defects in formation of the pancreatic exocrine and endocrine systems [16]. Endocrine differentiation is affected by Dicer1 loss early in organ development, before activation

Liver miRNAs and lipid metabolism

Once secreted from the islet, insulin and glucagon travel to the liver through the portal circulation where they control hepatic glucose and lipid metabolism. Liver insulin resistance plays an important role in the development of the metabolic syndrome. and dysregulation of miRNA expression potentially influences insulin resistance. Dicer1 deletion from the early postnatal liver resulted in profound hepatocyte apoptosis, steatosis and mild hypoglycemia [33]. The most highly expressed miRNA in

Adipose tissue miRNAs and energy metabolism

Fatty acids travel in lipoprotein particles from the liver to the adipose tissue where they are stored in lipid droplets. Knockdown of either DICER1 or RNASEN prevents in vitro differentiation of human multipotent stromal cells to adipocytes, implying that miRNAs might be important for adipogenesis [42]. The first indication that miRNAs might be important in adipose cell biology came from the observation that miRNA-143 is one of several miRNAs that are upregulated during differentiation of

Muscle and brain miRNAs and metabolic control

Muscle is a major site of glucose disposal and metabolism. Although there is substantial evidence demonstrating a role for miRNAs in muscle growth and development [52], little is known about miRNA regulation of muscle glucose metabolism. Dicer1 removal from cardiac progenitors, from adult hearts and from developing muscle all lead to tissue loss and death 53, 54, 55. The miRNA-1/206 and the miRNA-133a/133b families appear to be most important for muscle development and growth. These miRNAs are

Concluding remarks

It is now clear that gene regulatory mechanisms governed by miRNAs are important for the development and maintenance of metabolically active tissues. Furthermore, alteration in miRNA expression in several of these tissues can result in impaired glucose and lipid homeostasis through a wide range of mechanisms ranging from cell cycle control to exocytotic regulation. Unfortunately, the regulatory power that miRNAs exert through their large repertoire of target genes is the Achilles heel of miRNA

Acknowledgements

I am indebted to Michael German, Matthias Hebrok and Michael McManus for their help, support and advice. Postdoctoral fellowship awards 3-2004-276 and 10-2007-86 from Juvenile Diabetes Research Foundation allowed me to carry out studies in this field and for this I am grateful. This is a burgeoning field and as such there has been a huge increase in the number of publications over the past 5 years. This large number of exciting publications has made this article possible; however, the length of

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