# Defining the molecular regulation and physiological role of a novel lysosomal mechanism of adipocyte lipolysis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $538,357

## Abstract

Project Summary:
Adipose tissue is a dynamic energy depot that supports metabolic function and survival during fasting. When the
ability of adipocytes to dynamically release energy in the form of fatty acids is impaired, fat cells become
hypertrophied and develop ER stress, insulin resistance, express hypoxic signaling programs and inflammatory
mediators, all of which contribute to the pathobiology of cardiometabolic disease. The canonical view of
adipocyte energy balance is that insulin drives energy storage in lipids with feeding, while counterregulatory
hormones drive release of three fatty acid chains from each triglyceride molecule with fasting through the
sequential action of three lipases, including the rate-limiting adipose triglyceride lipase (ATGL). In preliminary
data contained in this grant proposal, our laboratory discovered evidence that fasting-lipolysis is largely
preserved when the canonical ATGL-dependent lipolytic pathway is targeted during prolonged fasting. Instead,
our preliminary data points to a critical role for a complementary, alternative pathway involving lysosomes and
the lysosomal lipase (lysosomal acid lipase-LIPA). Our preliminary data further demonstrate that members of
the MiT/TFE transcription factor family, including the master regulator of lysosomal biogenesis, TFEB, are
required for lipolysis with fasting. These preliminary data support the central hypothesis of this project: lysosomal
digestion of lipid in adipocytes is a critical mechanism of fatty acid release during fasting. In this proposal we
seek to leverage innovative methods, including inducible adipocyte targeted loss of function studies in vivo, state
of the art multi-omics studies of MiT/TFE transcription factor regulatory circuitry, and high-resolution imaging
mass spectrometry—which enables quantitative tracking of stable isotope lipid labels at the sub-organelle level—
to examine the underlying mechanisms and the physiological implications of this novel lipolytic pathway in
adipocytes. In Aim 1, we will define the molecular and cell biological mechanisms that govern mobilization of
fatty acids from adipocytes with fasting. In Aim 2, we will define the role of the lysosomal lipolysis pathway in
systemic lipid homeostasis and energy balance in the context of fasting and disease-relevant stressors of aging
and diet-induced obesity. Decades of data suggests that lipolysis in adipocytes, which is a major determinant of
circulating fatty acids and systemic lipid metabolism, is important to cardiometabolic diseases such as diabetes
mellitus. If our central hypothesis is correct, that an alternative lysosomal pathway is operative with fasting, then
our understanding of systemic fatty acid metabolism is incomplete. Completion of this project holds promise to
reorient our understanding of how adipocytes regulate systemic lipid metabolism and to determine whether this
core function is a determinant of metabolic disease.

## Key facts

- **NIH application ID:** 10979881
- **Project number:** 1R01DK137913-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Matthew Steinhauser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $538,357
- **Award type:** 1
- **Project period:** 2024-09-10 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979881

## Citation

> US National Institutes of Health, RePORTER application 10979881, Defining the molecular regulation and physiological role of a novel lysosomal mechanism of adipocyte lipolysis (1R01DK137913-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10979881. Licensed CC0.

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