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Published on: January 4, 2018
Hypothalamic miR-1983 Targets Insulin Receptor β and the Insulin-mediated miR-1983 Increase Is Blocked by Metformin
Jennifer A Chalmers1, Prasad S Dalvi1, Neruja Loganathan1
1Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Abstract:
MicroRNAs (miRNAs) expressed in the hypothalamus are capable of regulating energy balance and peripheral metabolism by inhibiting translation of target messenger RNAs (mRNAs). Hypothalamic insulin resistance is known to precede that in the periphery, thus a critical unanswered question is whether central insulin resistance creates a specific hypothalamic miRNA signature that can be identified and targeted. Here we show that miR-1983, a unique miRNA, is upregulated in vitro in 2 insulin-resistant immortalized hypothalamic neuronal neuropeptide Y-expressing models, and in vivo in hyperinsulinemic mice, with a concomitant decrease of insulin receptor β subunit protein, a target of miR-1983. Importantly, we demonstrate that miR-1983 is detectable in human blood serum and that its levels significantly correlate with blood insulin and the homeostatic model assessment of insulin resistance. Levels of miR-1983 are normalized with metformin exposure in mouse hypothalamic neuronal cell culture. Our findings provide evidence for miR-1983 as a unique biomarker of cellular insulin resistance, and a potential therapeutic target for prevention of human metabolic disease.
Insights
A novel microRNA, miR-1983, is elevated in cellular insulin resistance and detectable in human blood. This microRNA may serve as a biomarker and therapeutic target for metabolic diseases.
Area of Science:
- Neuroendocrinology
- Metabolic Regulation
- Molecular Biology
Background:
- Hypothalamic microRNAs (miRNAs) regulate energy balance and metabolism.
- Central insulin resistance precedes peripheral insulin resistance.
- Identifying a hypothalamic miRNA signature for insulin resistance is crucial.
Purpose of the Study:
- To determine if central insulin resistance generates a specific hypothalamic miRNA signature.
- To investigate the role of miR-1983 in hypothalamic insulin resistance.
- To assess miR-1983 as a potential biomarker and therapeutic target for metabolic disease.
Main Methods:
- In vitro studies using insulin-resistant hypothalamic neuronal models (NPY-expressing).
- In vivo studies in hyperinsulinemic mice.
- Detection and correlation analysis of miR-1983 in human blood serum.
- Assessment of metformin's effect on miR-1983 levels.
Main Results:
- miR-1983 was upregulated in insulin-resistant hypothalamic models and hyperinsulinemic mice.
- Insulin receptor β subunit protein decreased, correlating with miR-1983 levels.
- miR-1983 levels in human serum correlated with insulin and HOMA-IR.
- Metformin normalized miR-1983 levels in cell culture.
Conclusions:
- miR-1983 is a unique biomarker for cellular insulin resistance.
- miR-1983 is a potential therapeutic target for metabolic diseases.
- Hypothalamic miR-1983 alterations are linked to systemic insulin resistance.
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