# Discovery and characterization of a novel acylcarnitine transporter in brown adipocytes

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $272,125

## Abstract

Project Summary/Abstract
In the United States, 42% of the population is obese, and this obesity predisposes individuals for several
diseases including type 2 diabetes which affects 29 million Americans. One established mechanism for the
causal relationship between obesity and type 2 diabetes is the development of lipotoxicity, a state where excess
lipids build-up to cause increased ectopic lipid droplets, elevated plasma lipids, and subsequently, decreased
cellular insulin signaling. These plasma lipids that are increased with lipotoxicity include acylcarnitines, a key
intermediate in fatty acid oxidation. Acylcarnitines are an established biomarker of type 2 diabetes, hepatocellular
carcinoma, and cardiovascular disease, and are known to cause insulin resistance. Despite the known
importance of plasma acylcarnitines in the development of insulin resistance, we do not know how they are
imported into cells, how this uptake is regulated, or how imported acylcarnitines are metabolized once they enter
the cell from the circulatory system.
In this proposal we examine the regulation of acylcarnitine uptake by transporters we have identified through a
CRISPR/Cas9 screen. Through targeted knockout of these transporters, we will conduct cell culture experiments
to highlight the precise molecular pathways through which acylcarnitines enter the cell and signal for insulin
sensitivity. We will also explore tissue specific loss of acylcarnitines in mouse models to determine the
contribution of plasma acylcarnitine uptake on whole-body energy expenditure, glucose regulation, and plasma
lipid pools. Finally, we will determine how these transporters for plasma acylcarnitines are regulated in cell
culture and tissue samples from mice to establish potential therapeutic targets for the treatment of metabolic
disease.
The proposed work will address long-standing questions on the molecular regulation of plasma acylcarnitine
import, metabolism of acylcarnitines after entry into the cell, and the regulation of insulin sensitivity by
acylcarnitines. In terms of translatability, this work will generate a mechanistic understanding of how plasma
acylcarnitine abundance is controlled and how plasma acylcarnitines impact disease vulnerability to enable the
identification of new targets for the pharmacological treatment of obesity and diabetes.

## Key facts

- **NIH application ID:** 10500588
- **Project number:** 1R01DK133479-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Judith Anne Simcox
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $272,125
- **Award type:** 1
- **Project period:** 2022-08-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10500588

## Citation

> US National Institutes of Health, RePORTER application 10500588, Discovery and characterization of a novel acylcarnitine transporter in brown adipocytes (1R01DK133479-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10500588. Licensed CC0.

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