Article

Mammalian Genome

, 20:476

First online:

Obesity and genetics regulate microRNAs in islets, liver, and adipose of diabetic mice

  • Enpeng ZhaoAffiliated withBiochemistry Department, University of Wisconsin
  • , Mark P. KellerAffiliated withBiochemistry Department, University of Wisconsin
  • , Mary E. RabagliaAffiliated withBiochemistry Department, University of Wisconsin
  • , Angie T. OlerAffiliated withBiochemistry Department, University of Wisconsin
  • , Donnie S. StapletonAffiliated withBiochemistry Department, University of Wisconsin
  • , Kathryn L. SchuelerAffiliated withBiochemistry Department, University of Wisconsin
  • , Elias Chaibub NetoAffiliated withStatistics Department, University of Wisconsin
  • , Jee Young MoonAffiliated withStatistics Department, University of Wisconsin
  • , Ping WangAffiliated withBiostatistics and Medical Informatics, University of Wisconsin
    • , I-Ming WangAffiliated withRosetta Inpharmatics
    • , Pek Yee LumAffiliated withRosetta Inpharmatics
    • , Irena IvanovskaAffiliated withRosetta Inpharmatics
    • , Michele ClearyAffiliated withRosetta Inpharmatics
    • , Danielle GreenawaltAffiliated withRosetta Inpharmatics
    • , John TsangAffiliated withRosetta Inpharmatics
    • , Youn Jeong ChoiAffiliated withBiostatistics and Medical Informatics, University of Wisconsin
    • , Robert KleinhanzAffiliated withRosetta Inpharmatics
    • , Jin ShangAffiliated withMerck Research Laboratories
    • , Yun-Ping ZhouAffiliated withMerck Research Laboratories
    • , Andrew D. HowardAffiliated withMerck Research Laboratories
    • , Bei B. ZhangAffiliated withMerck Research Laboratories
    • , Christina KendziorskiAffiliated withBiostatistics and Medical Informatics, University of Wisconsin
    • , Nancy A. ThornberryAffiliated withMerck Research Laboratories
    • , Brian S. YandellAffiliated withStatistics Department, University of Wisconsin
    • , Eric E. SchadtAffiliated withSage Bionetworks
    • , Alan D. AttieAffiliated withBiochemistry Department, University of Wisconsin Email author 

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Abstract

Type 2 diabetes results from severe insulin resistance coupled with a failure of β cells to compensate by secreting sufficient insulin. Multiple genetic loci are involved in the development of diabetes, although the effect of each gene on diabetes susceptibility is thought to be small. MicroRNAs (miRNAs) are noncoding 19–22-nucleotide RNA molecules that potentially regulate the expression of thousands of genes. To understand the relationship between miRNA regulation and obesity-induced diabetes, we quantitatively profiled approximately 220 miRNAs in pancreatic islets, adipose tissue, and liver from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mice. More than half of the miRNAs profiled were expressed in all three tissues, with many miRNAs in each tissue showing significant changes in response to genetic obesity. Furthermore, several miRNAs in each tissue were differentially responsive to obesity in B6 versus BTBR mice, suggesting that they may be involved in the pathogenesis of diabetes. In liver there were approximately 40 miRNAs that were downregulated in response to obesity in B6 but not BTBR mice, indicating that genetic differences between the mouse strains play a critical role in miRNA regulation. In order to elucidate the genetic architecture of hepatic miRNA expression, we measured the expression of miRNAs in genetically obese F2 mice. Approximately 10% of the miRNAs measured showed significant linkage (miR-eQTLs), identifying loci that control miRNA abundance. Understanding the influence that obesity and genetics exert on the regulation of miRNA expression will reveal the role miRNAs play in the context of obesity-induced type 2 diabetes.