# Role of Hepatic RNA Silencing in Insulin Resistance and Obesity

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $351,000

## Abstract

Project Summary/Abstract
Drastic changes in lifestyle and dietary trends have triggered a rapid, worldwide epidemic of chronic metabolic
diseases including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD/steatosis). The need for
more effective treatments of T2D and metabolic diseases has never been more urgent.
 This proposal investigates the innovative hypothesis that T2D results from deregulated function of
hepatic Argonaute 2 (Ago2), a main component of the RNA-induced silencing complex (RISC). Our novel
preliminary data indicates hepatic Ago2 plays a central role in regulating mitochondrial function in the
pathogenesis of T2D. In mammals, there are four Argonaute family proteins that play crucial roles in RNA
silencing. Among them, Ago2 uniquely possesses endonuclease activity that is critical for the biogenesis of
specific miRNAs and for mRNA cleavage. In the hepatic Ago2-deficient state, expressions of miRNAs, which
are known to impair glucose metabolism, are selectively suppressed, whereas mRNAs enhancing
mitochondrial function are increased. Intriguingly, our preliminary results identified that metformin treatment
induces Ago2 functional changes associated with its endonuclease activity. These preliminary data suggest
unique and pivotal roles for hepatic Ago2 in regulating glucose homeostasis, leading us to hypothesize that
Ago2 regulates glucose and lipid metabolism in the liver through miRNA biogenesis and RNA silencing that
affects mitochondrial function. Further, we hypothesize that increased Ago2-mediated RNA silencing contribute
to hepatic steatosis and insulin resistance, and decreased Ago2 function mediates the therapeutic effect of
metformin.
 Studies in this proposal will: (1) determine the Ago2 endonuclease activity important in T2D
pathogenesis; (2) dissect Ago2 function in the therapeutic effect of metformin for improved glucose metabolism
in T2D; (3) delineate Ago2-dependent mRNA silencing critical in glycemic control in T2D and in metformin's
action.
 The goal of this application is to gain a clear mechanistic understanding of the role of the hepatic Ago2-
miRNA axis in the pathogenesis and in the treatment of T2D. The long-term goal of this program is to identify
novel preventive and therapeutic strategies for T2D.

## Key facts

- **NIH application ID:** 9974294
- **Project number:** 5R01DK107530-05
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Takahisa Nakamura
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,000
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974294

## Citation

> US National Institutes of Health, RePORTER application 9974294, Role of Hepatic RNA Silencing in Insulin Resistance and Obesity (5R01DK107530-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974294. Licensed CC0.

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