# Endothelial mineralocorticoid receptors in diet-induced skeletal muscle insulin resistance

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2022 · $397,048

## Abstract

Project Summary/Abstract
 Excess lipids increase the total intramyocellular lipid content and the ectopic fat storage resulting in
lipotoxicity and insulin resistance in skeletal muscles, which is one of the main targets of insulin and its action
is central for the maintenance of glucose homeostasis. Consumption of a diet high in fat and refined sugars, a
Western Diet (WD), activates mineralocorticoid receptors (MRs) to induce muscle lipid metabolic disorders and
insulin resistance. Recent data further indicate that cell specific endothelial cell (EC) MR (ECMR) activation
mediates WD-induced muscle lipid metabolism disorders, impaired insulin metabolic signaling, and tissue
insulin resistance. In this regard, ECMR activation increase CD36 expression in skeletal muscle arterioles and
tissues, which promotes excessive free fatty acid trafficking across the muscle vasculature, leading to skeletal
muscle lipid accumulation, CD36 palmitoylation and insulin resistance. There is a relationship between
microvascular endothelial dysfunction and muscle metabolic disorders and insulin resistance through
exosomes. Recent data suggest that EC derived exosomal proteins, such as exosomal CD36, can promote
lipid accumulation and metabolic disorders. Upon being released from ECs, exosomal CD36 can be up-taken
by the neighboring skeletal muscle and thus promote muscle lipid accumulation. The hypothesis of this
application is that activation of ECMRs induces EC CD36 expression and release of EC-derived
exosomal CD36 which increases free fatty acid uptake in ECs and translocation to skeletal muscle
cells, leading to skeletal muscle intramyocellular lipid deposits and insulin resistance. Objective 1 of
this application is to understand the role and mechanisms of ECMR signaling on CD36 expression, free fatty
acid uptake in ECs and skeletal muscle cells, and related muscle lipid deposition and insulin resistance.
Objective 2 of this application is to investigate the role and mechanisms of enhanced ECMR signaling on the
EC-derived exosomal CD36 release and its role in facilitating increased skeletal muscle cell CD36 to further
promote muscle fatty acid uptake, IMC lipid deposition and insulin resistance. Accordingly, in vitro cell treated
with free fatty acid and in vivo mice fed a WD will be used to set up a model of ECMR/ECCD36 activation,
obesity and insulin resistance. The proposed work should provide a better understanding the role of ECMRs
and EC exosomal CD36 in the development of skeletal muscle insulin resistance and provide an important
biomarker for the early diagnosis and prevention of this increasing cause of diabetes.

## Key facts

- **NIH application ID:** 10308420
- **Project number:** 5R01DK124329-02
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Guanghong Jia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $397,048
- **Award type:** 5
- **Project period:** 2020-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308420

## Citation

> US National Institutes of Health, RePORTER application 10308420, Endothelial mineralocorticoid receptors in diet-induced skeletal muscle insulin resistance (5R01DK124329-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10308420. Licensed CC0.

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