# Distinct functions of adipocyte-derived FGF21 in obesity

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $485,375

## Abstract

Title: Distinct functions of adipocyte-derived FGF21 in obesity
Summary
Obesity is rapidly reaching epidemic proportions, with an urgent need for novel strategies for weight loss.
Fibroblast growth factor 21 (FGF21) is a hormone derived from the liver and adipose tissue that plays a
beneficial role in energy homeostasis when given pharmacologically, but is paradoxically activated by both
fasting and feeding signals. Obesity is associated with elevated levels of circulating FGF21 in rodents and
humans, which correlates with adiposity and adipose tissue FGF21 mRNA levels, suggesting that obesity-
associated FGF21 derives from adipose tissue. While the beneficial effects of pharmacological FGF21 and
hepatic FGF21 on energy metabolism are generally accepted, a clearly defined role for adipocyte-derived
FGF21 has not been established, especially in the context of obesity. Preliminary data suggest that adipocyte-
derived FGF21 promotes deleterious effects on body weight and glucose metabolism, which is in stark contrast
with the beneficial effects observed for pharmacological and hepatic-derived FGF21. Mice deficient in
adipocyte-derived FGF21 (FAKO mice) are protected from diet-induced obesity, have less body fat, and exhibit
increased energy expenditure and improved insulin sensitivity over wild-type controls. Thus, the hypotheses of
this proposal are that: (1) the development of obesity requires FGF21; and (2) adipocyte-derived FGF21 is
functionally distinct from hepatic-derived FGF21, and could therefore be targeted pharmacologically. Aim 1 will
determine whether adipocyte-derived FGF21 is sufficient or required for obesity-associated adipose tissue
expansion and associated comorbidities. We will use several loss- and gain-of-function models of genetically-
perturbed mice as well as fat transplantation techniques to ascertain whether adipocyte-derived FGF21 is
important for the development and/or maintenance of obesity. In Aim 2, potential mechanisms by which
adipose FGF21 modulates local and systemic metabolism will be examined. This will include an assessment of
a role for adipocyte-derived FGF21 in thermoregulation, in autocrine signaling in adipose tissue, in systemic
signaling in traditional FGF21 target tissues, and the potential for adipocyte-derived and hepatic-derived
FGF21 to be differentially processed posttranslationally, which could impact their ability to target local or distal
tissues. Reconciling the differences between the beneficial effects of hepatic FGF21 on energy metabolism
and the detrimental effects of adipocyte FGF21 in obesity could increase our understanding of adipocyte
metabolism in obesity. Such knowledge could lead to novel therapeutic strategies to combat obesity, such as
targeting adipocyte-derived FGF21.

## Key facts

- **NIH application ID:** 10799413
- **Project number:** 1R01DK135756-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Laura J. den Hartigh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $485,375
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799413

## Citation

> US National Institutes of Health, RePORTER application 10799413, Distinct functions of adipocyte-derived FGF21 in obesity (1R01DK135756-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10799413. Licensed CC0.

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