# Regulation of Metabolism by FGF21

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $655,744

## Abstract

PROJECT SUMMARY / ABSTRACT
The ever-increasing incidence of obesity and type 2 diabetes has led to a concurrent increase in metabolic
associated liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and
metabolic dysfunction-associated steatohepatitis (MASH). The presence of these diseases increases the risk of
progression to liver cirrhosis and hepatocellular carcinoma. However, there are currently no FDA approved drugs
for the treatment of MASLD or MASH. Fibroblast growth factor 21 (FGF21) has shown efficacy in reducing liver
fat and fibrosis in pre-clinical models, leading to the development of a promising class of long-lived FGF21
analogs as pharmaceutical treatments for MASH. Recently, our lab demonstrated that FGF21 reduces body
weight and increases energy expenditure via action in a genetically defined (Vglut2+) neuronal population. Our
new preliminary data suggests that FGF21’s effect on hepatic triglyceride levels and fibrosis, but not cholesterol
content, is also mediated through Vglut2+ neurons. Our central hypothesis is that FGF21 reverses MASH by
signaling to glutamatergic neurons to increase sympathetic nerve activity to the liver to lower hepatic steatosis
and fibrosis, and that FGF21 action on hepatocytes reduces hepatic cholesterol levels This proposal seeks to
determine the mechanisms by which FGF21 and its analogs reverse MASH by 1) determining the direct central
target of FGF21 that mediates the resolution of MASH, 2) determine how central versus hepatic FGF21 signaling
alone or in combination functions to reverse hepatic steatosis, and 3) determine the contribution and
mechanisms of FGF21-mediated changes in liver-innervating neurons to regulate liver function. Proposed
studies employ a suite of genetic mouse models to selective abolish or add-back β-klotho (the obligate co-
receptor for FGF21) from specific cell types with a physiologically relevant dietary MASH model to dissect the
contributions of Vglut2+ neurons and hepatocytes in the effects of FGF21. Together, these studies will determine
how FGF21 reverses MASH and may reveal novel pathways that could be selectively targeted for future
therapeutic strategies.

## Key facts

- **NIH application ID:** 10996942
- **Project number:** 2R01DK106104-10
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Matthew Joseph Potthoff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $655,744
- **Award type:** 2
- **Project period:** 2015-07-15 → 2025-01-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996942

## Citation

> US National Institutes of Health, RePORTER application 10996942, Regulation of Metabolism by FGF21 (2R01DK106104-10). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10996942. Licensed CC0.

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