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

Biochemistry Department, University of Wisconsin, Madison, WI 53706, USA.
Mammalian Genome (Impact Factor: 3.07). 10/2009; 20(8):476-85. DOI: 10.1007/s00335-009-9217-2
Source: PubMed


Type 2 diabetes results from severe insulin resistance coupled with a failure of b 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.

Download full-text


Available from: I-Ming Wang
  • Source
    • "The panomics approach is relatively new to the study of PTSD and deployment-related outcomes, but it is not new to medical science. Significant success in identification of biomarkers and treatments in other complex disorders such as irritable bowel disease (Dudley et al., 2011; Jostins et al., 2012), obesity (Cotsapas et al., 2009; Davis et al., 2012; Mehrabian et al., 2005; Yang et al., 2009; Zhao et al., 2009), diabetes (Dastani et al., 2012; Davis et al., 2012; Drake, Schadt, Davis, & Lusis, 2005; Kang et al., 2012; Keller et al., 2008; Prokunina-Olsson, Kaplan, Schadt, & Collins, 2009; Saxena et al., 2012; Schadt et al., 2003; Zhong, Beaulaurier, et al., 2010), heart disease (Derry et al., 2010; Drake, Schadt, & Lusis, 2006; Ganesh et al., 2013; Keating et al., 2008; Schwartz, Schwartz, Horvath, Schadt, & Lee, 2012; Vergeer et al., 2010), and Alzheimer's disease (Zhang et al., 2013) has been achieved using this molecular approach. Given that many of these diseases have considerable environmental antecedents* many of them highly relevant to post-deployment health outcomes*the application of these methods to the study of service persons and combat veterans with mental and physical illness is timely and appropriate. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Posttraumatic stress disorder (PTSD) and other deployment-related outcomes originate from a complex interplay between constellations of changes in DNA, environmental traumatic exposures, and other biological risk factors. These factors affect not only individual genes or bio-molecules but also the entire biological networks that in turn increase or decrease the risk of illness or affect illness severity. This review focuses on recent developments in the field of systems biology which use multidimensional data to discover biological networks affected by combat exposure and post-deployment disease states. By integrating large-scale, high-dimensional molecular, physiological, clinical, and behavioral data, the molecular networks that directly respond to perturbations that can lead to PTSD can be identified and causally associated with PTSD, providing a path to identify key drivers. Reprogrammed neural progenitor cells from fibroblasts from PTSD patients could be established as an in vitro assay for high throughput screening of approved drugs to determine which drugs reverse the abnormal expression of the pathogenic biomarkers or neuronal properties.
    Full-text · Article · Aug 2014 · European Journal of Psychotraumatology
  • Source
    • "We performed small RNA sequencing on total RNA from islets of 12-week-old ob/ob mice (Table S1 available online). Consistent with results by Zhao et al. (2009), expression of miR-184 was the most reduced miRNA identified (Figure 1A; Table S1). We then measured miR-184 in the islets of ob/ob mice from age 4–16 weeks and observed the decrease in expression starting at 8 weeks of age with the onset of resistance (Figures 1B, S1A, and S1B). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic β cells adapt to compensate for increased metabolic demand during insulin resistance. Although the microRNA pathway has an essential role in β cell proliferation, the extent of its contribution is unclear. Here, we report that miR-184 is silenced in the pancreatic islets of insulin-resistant mouse models and type 2 diabetic human subjects. Reduction of miR-184 promotes the expression of its target Argonaute2 (Ago2), a component of the microRNA-induced silencing complex. Moreover, restoration of miR-184 in leptin-deficient ob/ob mice decreased Ago2 and prevented compensatory β cell expansion. Loss of Ago2 during insulin resistance blocked β cell growth and relieved the regulation of miR-375-targeted genes, including the growth suppressor Cadm1. Lastly, administration of a ketogenic diet to ob/ob mice rescued insulin sensitivity and miR-184 expression and restored Ago2 and β cell mass. This study identifies the targeting of Ago2 by miR-184 as an essential component of the compensatory response to regulate proliferation according to insulin sensitivity.
    Full-text · Article · Dec 2013 · Cell metabolism
  • Source
    • "Because muscle tissue accounts for over 85-90% of the impairment in total body glucose disposal in individuals with T2D [67,68], understanding of the mechanism of insulin resistance in muscle tissue are of importance for the prevention and cure of T2D. In terms of adipose tissue and liver, several studies suggested important roles of microRNAs in insulin resistance [69-72]. For example, mir-29 is upregulated in diabetic rats and is linked to insulin resistance in 3T3-L1 adipocytes [69]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic inflammation is fundamental for the induction of insulin resistance in the muscle tissue of vertebrates. Although several miRNAs are thought to be involved in the development of insulin resistance, the role of miRNAs in the association between inflammation and insulin resistance in muscle tissue is poorly understood. Herein, we investigated the aberrant expression of miRNAs by conducting miRNA microarray analysis of TNF-α-treated mouse C2C12 myotubes. We identified two miRNAs that were upregulated and six that were downregulated by a >1.5-fold change compared to normal cells. Among the findings, qRT-PCR analysis confirmed that miR-494 is consistently upregulated by TNF-α-induced inflammation. Overexpression of miR-494 in CHOIR/IRS1 and C2C12 myoblasts suppressed insulin action by down-regulating phosphorylations of GSK-3α/β, AS160 and p70S6K, downstream of Akt. Moreover, overexpression of miR-494 did not regulate TNF-α-mediated inflammation . Among genes bearing the seed site for miR-494, RT-PCR analysis showed that the expression of Stxbp5, an inhibitor of glucose transport, was downregulated following miR-494 inhibition. In contrast, the expression of PTEN decreased in the cells analyzed, thus showing that both positive and negative regulators of insulin action may be simultaneously controlled by miR-494. To investigate the overall effect of miR-494 on insulin signaling, we performed a PCR array analysis containing 84 genes related to the insulin signaling pathway, and we observed that 25% of genes were downregulated (P<0.05) and 11% were upregulated (P<0.05). These results confirm that miR-494 might contribute to insulin sensitivity by positive and negative regulation of the expression of diverse genes. Of note, PCR array data showed downregulation of Slc2A4, a coding gene for Glut4. Altogether, the present study concludes that the upregulation of miR-494 expression by TNF-α-mediated inflammation exacerbates insulin resistance. Therefore, we suggest that miR-494 could prove an important target for the diagnosis and therapy of inflammation-mediated insulin resistance in muscle.
    Full-text · Article · Dec 2013 · PLoS ONE
Show more