# Role of extracellular vesicles in the regulation of immunometabolism in obesity

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $588,256

## Abstract

Project Summary
The worldwide prevalence of obesity has reached pandemic proportions. Obesity has strong inflammatory
underpinnings, which are associated with the development of type 2 diabetes (T2D) and non-alcoholic
steatohepatitis (NASH). However, the mechanisms by which obesity provokes aberrant inflammation are not
clearly defined. In this study, we aim to demonstrate that in obesity, the mTOR pathway enhances the
biogenesis and secretion of pro-inflammatory extracellular vesicles (EVs) carrying a distinct set of
extracellular RNAs (exRNAs) from hepatocytes and that these hepatocyte-derived EVs (H-EVs) cause the
aberrant inflammation.
EVs, including exosomes (30–150 nm) and microvesicles (100–1000 nm), are released from many cell types
into the extracellular space and are distributed in body fluids. These EVs are taken up by neighboring or
distant cells and subsequently modulate functions of recipient cells. Using novel computational methods9, we
identified strong associations between human genetic variations of genes regulating EV biogenesis and
metabolic syndrome, particularly T2D. Our analyses of EVs from adolescent obese patients undergoing
bariatric surgery have shown that serum EV concentration is inversely correlated to metabolic improvements
in insulin sensitivity and inflammation post-surgery, with unique EVs’ exRNA profiles. Further, our newly
established mouse model that permits monitoring of specific cell type-derived EVs in vivo indicates that in
obesity, H-EVs behave like a pathogen recognized by macrophages and induce inflammation. Mechanistically,
we found that in hepatocytes, the insulin-mTOR pathway enhances secretion of EVs and that insulin-
stimulated EVs are more pro-inflammatory in activating macrophages. We have also discovered that a
component of the RNA silencing machinery is a mediator of the pro-inflammatory EVs and is required for the
EV-induced macrophage activation. These preliminary data suggest unique and pivotal roles for H-EVs,
leading us to hypothesize that during the development of hyperinsulinemia, hepatocytes secrete
pathologic EVs carrying unique exRNAs which are sensed by recipient macrophages, promoting
aberrant inflammation.
Studies in this proposal will: (1) define the molecular pathway that confers the proinflammatory trait to the H-
EVs, (2) determine the role of RNA silencing machinery in macrophages as a mediator of pro-inflammatory
EVs, and (3) evaluate the role of EVs in immunometabolism in human obese patients.
By utilizing our novel mouse models coupled with access to human samples, our systematical approaches
will demonstrate novel mechanisms concerning how the pathogenicity of H-EVs is involved in the
development of inflammation in hyperinsulinemia and obesity.

## Key facts

- **NIH application ID:** 10439659
- **Project number:** 5R01DK123181-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Takahisa Nakamura
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $588,256
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439659

## Citation

> US National Institutes of Health, RePORTER application 10439659, Role of extracellular vesicles in the regulation of immunometabolism in obesity (5R01DK123181-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10439659. Licensed CC0.

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