# Role of ATGL and lipid metabolism in healthspan

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $318,776

## Abstract

The biological underpinnings through which changes in diet or exercise influence healthspan - increased
lifespan in the absence of disease - are not fully understood. Recent data in flies and worms have highlighted
a potential role for lipolysis, the catabolism of triacylglycerol (TAG) stored within lipid droplets (LDs), as a factor
that promotes healthspan. However, the mechanisms linking lipolysis to alterations in healthspan are not
known. In addition, no studies have evaluated the role of lipolysis in healthspan regulation in mammals or the
interaction of lipolysis and diet, which largely determines the composition of LDs and, therefore, their signaling
properties. Thus, the objective of this application is to define the mechanisms through which lipolysis
influences healthspan and to determine the contribution of dietary lipid composition to these effects. We
hypothesize that lipolysis is a key signaling node that drives healthspan through alterations in fatty acid
signaling. We base this hypothesis on preliminary data from our laboratory defining a signaling axis linking
adipose triglyceride lipase (ATGL)-catalyzed lipolysis to sirtuin 1 (SIRT1) activity and downstream signaling to
activate forkhead box protein 01 (FOXO1). We also show that overexpression of the Drosophila homolog of
ATGL, brummer (Bmm), increases lifespan consistent the known roles of SIRT1 and FOXO1 as key regulators
of lifespan. To test our hypothesis, we will utilize the strengths of both Drosophila and mouse models to test
the following specific aims: Aim 1: To delineate the signaling pathway through which lipolysis influences
healthspan in Drosophila. We will use Drosophila models to dissect the linearity of the Bmm-Sir2 (fly SIRT1
homolog)-dFOXO (fly FOXO1 homolog) signaling axis in regulating healthspan. Aim 2: To determine the
interactions between diet and ATGL on healthspan in mice. These studies will explore the synergy
between dietary lipid composition and ATGL overexpression on lifespan and aging-related declines in
metabolism in mice. Aim 3: To characterize the interaction between ATGL and autophagy. In this aim,
will test the effects of ATGL on autophagy and the role of autophagy in mediating the signaling and lifespan
extending effects of ATGL/Bmm in both fly and mammalian models. These studies will be the first to
comprehensively define the role of ATGL-catalyzed lipolysis in healthspan and how it interacts other
physiological factors involved in lifespan regulation. These studies are innovative because they will use novel
fly and mouse models to link individual factors known to influence lifespan such as diet into a cohesive model
that better explains healthspan regulation. The proposed work is significant because it will greatly advance
our understanding into the understudied area of lipid metabolism as a factor contributing to aging and will
provide substantial insights into new or improved dietary, behavorial or pharmaceutical avenues to promote
healthsp...

## Key facts

- **NIH application ID:** 10131076
- **Project number:** 5R01AG055452-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Douglas G Mashek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $318,776
- **Award type:** 5
- **Project period:** 2017-09-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131076

## Citation

> US National Institutes of Health, RePORTER application 10131076, Role of ATGL and lipid metabolism in healthspan (5R01AG055452-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10131076. Licensed CC0.

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