Acute suppression of insulin resistance-associated hepatic miR-29 in vivo improves glycemic control in adult mice

Hung Yu-Han, Matt Kanke, C. Lisa Kurtz, Rebecca Cubitt, Rodica P. Bunaciu, Ji Miao, Liye Zhou, James L. Graham, M. Mahmood Hussain, Peter J Havel, Sudha Biddinger, Phillip J. White, Praveen Sethupathy

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

MicroRNAs (miRNAs) are important posttranscriptional regulators of metabolism and energy homeostasis. Dysregulation of certain miRNAs in the liver has been shown to contribute to the pathogenesis of Type 2 diabetes (T2D), in part by impairing hepatic insulin sensitivity. By small RNA-sequencing analysis, we identified seven hepatic miRNAs (including miR- 29b) that are consistently aberrantly expressed across five different rodent models of metabolic dysfunction that share the feature of insulin resistance (IR). We also showed that hepatic miR-29b exhibits persistent dysregulation during disease progression in a rat model of diabetes, UCD-T2DM. Furthermore, we observed that hepatic levels of miR-29 family members are attenuated by interventions known to improve IR in rodent and rhesus macaque models. To examine the function of the miR-29 family in modulating insulin sensitivity, we used locked nucleic acid (LNA) technology and demonstrated that acute in vivo suppression of the miR-29 family in adult mice leads to significant reduction of fasting blood glucose (in both chow-fed lean and high-fat diet-fed obese mice) and improvement in insulin sensitivity (in chow-fed lean mice). We carried out whole transcriptome studies and uncovered candidate mechanisms, including regulation of DNA methyltransferase 3a (Dnmt3a) and the hormone-encoding gene Energy homeostasis associated (Enho). In sum, we showed that IR/T2D is linked to dysregulation of hepatic miR-29b across numerous models and that acute suppression of the miR-29 family in adult mice leads to improved glycemic control. Future studies should investigate the therapeutic utility of miR-29 suppression in different metabolic disease states.

Original languageEnglish (US)
Pages (from-to)379-389
Number of pages11
JournalPhysiological Genomics
Volume51
Issue number8
DOIs
StatePublished - Jan 1 2019

Fingerprint

Insulin Resistance
Liver
MicroRNAs
Type 2 Diabetes Mellitus
Rodentia
Homeostasis
RNA Sequence Analysis
Obese Mice
Metabolic Diseases
High Fat Diet
Macaca mulatta
Transcriptome
Energy Metabolism
Disease Progression
Blood Glucose
Fasting
Hormones
Technology
Genes
Therapeutics

Keywords

  • Enho
  • Insulin resistance
  • Liver
  • MicroRNA-29 (miR-29)
  • UCDT2DM

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Acute suppression of insulin resistance-associated hepatic miR-29 in vivo improves glycemic control in adult mice. / Yu-Han, Hung; Kanke, Matt; Kurtz, C. Lisa; Cubitt, Rebecca; Bunaciu, Rodica P.; Miao, Ji; Zhou, Liye; Graham, James L.; Hussain, M. Mahmood; Havel, Peter J; Biddinger, Sudha; White, Phillip J.; Sethupathy, Praveen.

In: Physiological Genomics, Vol. 51, No. 8, 01.01.2019, p. 379-389.

Research output: Contribution to journalArticle

Yu-Han, H, Kanke, M, Kurtz, CL, Cubitt, R, Bunaciu, RP, Miao, J, Zhou, L, Graham, JL, Hussain, MM, Havel, PJ, Biddinger, S, White, PJ & Sethupathy, P 2019, 'Acute suppression of insulin resistance-associated hepatic miR-29 in vivo improves glycemic control in adult mice', Physiological Genomics, vol. 51, no. 8, pp. 379-389. https://doi.org/10.1152/physiolgenomics.00037.2019
Yu-Han, Hung ; Kanke, Matt ; Kurtz, C. Lisa ; Cubitt, Rebecca ; Bunaciu, Rodica P. ; Miao, Ji ; Zhou, Liye ; Graham, James L. ; Hussain, M. Mahmood ; Havel, Peter J ; Biddinger, Sudha ; White, Phillip J. ; Sethupathy, Praveen. / Acute suppression of insulin resistance-associated hepatic miR-29 in vivo improves glycemic control in adult mice. In: Physiological Genomics. 2019 ; Vol. 51, No. 8. pp. 379-389.
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AU - Miao, Ji

AU - Zhou, Liye

AU - Graham, James L.

AU - Hussain, M. Mahmood

AU - Havel, Peter J

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AU - White, Phillip J.

AU - Sethupathy, Praveen

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