# Role of GDF15 and its receptor in the CNS regulation of food intake and body weight

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $465,607

## Abstract

Project Summary/Abstract
 Obesity remains one of the largest unmet medical needs facing the US healthcare system. More than one
in three adults in the US are obese and these rates continue to increase with the most severe category of
obesity unfortunately growing the fastest. It is hard to overstate the human and monetary costs to the
individuals impacted and society as a whole. It remains that very few of these individuals receive effective
therapies. The existing behavioral interventions have limited efficacy. While the approved pharmacological
therapies are more successful, none of the currently approved therapies produce even 10% sustained body
weight loss on a placebo-adjusted basis. Consequently, there is still an enormous need for additional
pharmacological treatments for individuals with obesity.
 Growth differentiation factor 15 is a member of the TGFβ superfamily that has been linked to the anorexia
and weight loss that occurs with some cancers. This launched a number of programs to harness GDF15
analogues as obesity therapeutics and to identify the receptor that mediates these effects. Such efforts
culminated in a series of 4 high-profile papers published in late 2017 that each identified GDNF family receptor
α-like (GFRAL) as a high affinity receptor for GDF15 and is absolutely required for the potent effects of GDF15
to reduce food intake and body weight. Interestingly, GFRAL is almost exclusively expressed in the CNS.
Moreover, its distribution in the CNS is almost entirely limited to a brainstem area termed the area postrema
which sits outside the blood-brain barrier.
 Given the powerful weight loss effects of GDF15 mediated by this small population of neurons, it points to a
very important role of these neurons to regulate food intake and energy balance. We have built state-of-the-art
mouse models that will allow us to selectively identify, track and manipulate these neurons. To that end, we
will identify the projections from these neurons both within the caudal portion of the brainstem and to
hypothalamic areas that have been linked to the regulation of body weight. We will also use these tools to
selectively activate or silence these neurons and assess their role in normal control of energy balance and to
mediate the effects of other weight loss manipulations. This work has enormous significance and novelty.
GDF15 is one of the most promising new treatment strategies for obese individuals. Maybe even more
importantly, the potent effects of GDF15 point to a novel CNS circuit engaged from a very small population of
neurons located in the area postrema. Establishing components of this circuit and key aspects of GDF15
biology will maximize the potential utility of GDF15 as a therapeutic and identify new targets that target key
components of this system.

## Key facts

- **NIH application ID:** 10070103
- **Project number:** 5R01DK119188-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** RANDY J SEELEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $465,607
- **Award type:** 5
- **Project period:** 2019-01-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070103

## Citation

> US National Institutes of Health, RePORTER application 10070103, Role of GDF15 and its receptor in the CNS regulation of food intake and body weight (5R01DK119188-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10070103. Licensed CC0.

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