# The role of AgRP/Auga-ALK pathway in FGF21's brain action on aging

> **NIH NIH P01** · YALE UNIVERSITY · 2024 · $550,744

## Abstract

Abstract- Project 3: The role of AgRP/Augα-ALK pathway in FGF21’s brain action on aging
During the past 5 years, we have shown that systemic adaptation to calorie restriction is hinging on appropriate
hypothalamic circuit activity and integrity. We specifically observed that these parameters impacted by FGF21
are critically regulated by hypothalamic AgRP neurons, which themselves are under the control of FGF21.
FGF21 induces activation of these hypothalamic neurons, which results in altered functional connectivity of
hypothalamic circuits in support of behavior and autonomic regulation. In line with the involvement with FGF21’s
action, our preliminary studies demonstrated that impaired AgRP circuit integrity shortens mean lifespan of male
mice when fed ad-libitum. Strikingly, however, shorter lifespan of AgRP-impaired animals showed significantly
lower disease burden, including dramatic lower incidence of neoplastic events in these animals. In pursuit of
this paradoxical outcome, we have investigated mechanisms that are innate to AgRP neurons with relevance to
cancer development. In collaboration between the labs of the PIs (Tamas Horvath and Joseph Schlessinger),
we unmasked a previously unsuspected cancer-related cellular signaling modality between AgRP neurons and
cells in the paraventricular nucleus in control of systemic energy and glucose metabolism. We found that AgRP
neurons metabolic state-dependently express Augmentor α (Augα), a recently discovered ligand of the receptor
tyrosine kinase, ALK. ALK is expressed in the hypothalamic paraventricular nucleus, and, we found these cells
to be innervated by AgRP fibers originating in the arcuate nucleus. Knock down of Augα resulted in thinness,
which replicated the phenotype of ALK knockout animals. Our preliminary single cell RNAseq studies also
identified that the AgRP/Augα-ALK pathways is parallel but not overlapping in the PVN with that of AgRP-MC4R
pathway. Thus, we identified a novel signaling modality downstream of FGF21, which employs AgRP neurons
and a pathway (Augα-ALK) shown to be co-opted in etiology of multiple cancers. These observations gave
impetus to the central hypothesis of this project, which is that the Augα-ALK pathways originating in the
hypothalamic AgRP neurons impacts systemic action of FGF21, and, that this pathway is involved in AgRP circuit
integrity-dependent propagation of cancer development and lifespan.
The following Specific Aims will test these hypotheses:
Specific Aim 1 will determine whether Augα obstructs calorie restriction and FGF21-induced behavioral- and
peripheral tissue adaptations mediated by AgRP neurons.
Specific Aim 2 will assess the role of AgRP/Augα-ALK signaling pathway in in the effect of calorie restriction and
FGF21 on hippocampal and cortical circuit integrity.
Specific Aim 3 will interrogate the role of AgRP/Augα-ALK signaling pathway in lifespan in ad libitum fed, calorie
restricted and/or FGF21 treated mice.
The execution of these studie...

## Key facts

- **NIH application ID:** 10889155
- **Project number:** 5P01AG051459-08
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** TAMAS L HORVATH
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $550,744
- **Award type:** 5
- **Project period:** 2016-09-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889155

## Citation

> US National Institutes of Health, RePORTER application 10889155, The role of AgRP/Auga-ALK pathway in FGF21's brain action on aging (5P01AG051459-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10889155. Licensed CC0.

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