# Impact of the FGF21-Adiponectin-Ceramide Axis on Healthspan

> **NIH NIH P01** · YALE UNIVERSITY · 2020 · $335,325

## Abstract

Project 3: Impact of the FGF21-Adiponectin-Ceramide Axis on Healthspan
Abstract
Adipocytes secrete numerous lipid and protein factors with profound effects on systemic energy homeostasis.
One such adipokine that we first identified in the early 1990's, adiponectin (previously referred to as Acrp30),
has garnered significant attention as a potent mediator of insulin sensitivity and cell survival. FGF21 is another
factor released by a number of cell types (including adipocytes) that has beneficial effects on metabolism. In
genetically diabetic and diet-induced obese mice, FGF21 lowers blood glucose levels and enhances insulin
sensitivity only when adiponectin is functionally present. We have shown that both FGF21 as well as
adiponectin lower systemic and tissue levels of ceramides, a class of lipids that has been tightly linked to
insulin resistance, inflammation and apoptosis. FGF21 is also a potent secretagogue for adiponectin in
adipocytes. This is also in line with two recent papers that argue that the FGF21 receptors, FGFR1 and -
klotho, exert their primary effects through their presence in adipocytes. Our colleagues Kliewer and
Mangesldorf in Project 1 have previously demonstrated that FGF21 overexpressing mice show longer lifespan
in mice. Additional clinical data suggests that adiponectin may be a longevity gene. Based on this broad set of
preliminary data that argues for the FGF21-adiponectin axis to be a major player in health-span and longevity,
we propose the hypothesis that FGF21, via adiponectin, lowers age-related `lipotoxicity' and controls metabolic
health- and lifespan by effectively lowering systemic and tissue ceramide levels. We are in a unique position to
experimentally test this hypothesis, because the necessary mouse models to address this question have just
recently become available. Teaming up with the 3 other laboratories that are part of this PPG, each bringing a
unique tool set and expertise to the table, allows us to shed light on this very important axis with major
implications for health-span and longevity. Specifically, we will address this topic with 3 distinct Aims. In
Specific Aim 1, we will establish whether adiponectin has an effect on health-span. This has never been tested
preclinically. We will systemically analyze thymic lymphopoiesis and assess T cell repertoire diversity (Project
2) and mitochondrial function (Project 4) as a function of age and adiponectin. In Specific Aim 2, we will
determine the contributions of adiponectin on FGF21-mediated healthspan and lifespan. We will examine the
effects of the presence and absence of adiponectin on FGF21-mediated benefits on aging in the context of
FGF21 transgenic mice. This aim will be performed in close collaboration with Project 1 and Core B. In
Specific Aim 3, we will evaluate whether FGF21/adiponectin mediated lowering of age-related increase in
ceramides controls adipose tissue inflammation and functional decline. We already have generated inducible
mode...

## Key facts

- **NIH application ID:** 9938380
- **Project number:** 5P01AG051459-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** PHILIPP E SCHERER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,325
- **Award type:** 5
- **Project period:** — → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938380

## Citation

> US National Institutes of Health, RePORTER application 9938380, Impact of the FGF21-Adiponectin-Ceramide Axis on Healthspan (5P01AG051459-05). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/9938380. Licensed CC0.

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