mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia
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Updated: Dec 29, 2025
Measuring the Rate of Lipolysis in Ex Vivo Murine Adipose Tissue and Primary Preadipocytes Differentiated In Vitro
Published on: March 17, 2023
Lauren M Paolella1, Sarmistha Mukherjee2, Cassie M Tran2
1Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Objective:
Pharmacological agents targeting the mTOR complexes are used clinically as immunosuppressants and anticancer agents and can extend the lifespan of model organisms. An undesirable side effect of these drugs is hyperlipidemia. Although multiple roles have been described for mTOR complex 1 (mTORC1) in lipid metabolism, the etiology of hyperlipidemia remains incompletely understood. The objective of this study was to determine the influence of adipocyte mTORC1 signaling in systemic lipid homeostasis in vivo.
Methods:
We characterized systemic lipid metabolism in mice lacking the mTORC1 subunit Raptor (RaptoraKO), the key lipolytic enzyme ATGL (ATGLaKO), or both (ATGL-RaptoraKO) in their adipocytes.
Results:
Mice lacking mTORC1 activity in their adipocytes failed to completely suppress lipolysis in the fed state and displayed prominent hypertriglyceridemia and hypercholesterolemia. Blocking lipolysis in their adipose tissue restored normal levels of triglycerides and cholesterol in the fed state as well as the ability to clear triglycerides in an oral fat tolerance test.
Conclusions:
Unsuppressed adipose lipolysis in the fed state interferes with triglyceride clearance and contributes to hyperlipidemia. Adipose tissue mTORC1 activity is necessary for appropriate suppression of lipolysis and for the maintenance of systemic lipid homeostasis.
Insights
mTORC1 signaling in adipocytes is crucial for suppressing lipolysis and maintaining healthy lipid levels. Disrupting this pathway leads to hyperlipidemia, characterized by high triglycerides and cholesterol.
Area of Science:
- Cell Biology
- Metabolic Research
- Lipid Metabolism
Background:
- mTORC1 signaling plays a role in lipid metabolism, but its precise function in hyperlipidemia is unclear.
- mTORC1 inhibitors are used clinically but cause hyperlipidemia as a side effect.
Purpose of the Study:
- To investigate the role of adipocyte mTORC1 signaling in systemic lipid homeostasis.
- To elucidate the mechanisms by which mTORC1 influences lipid metabolism in vivo.
Main Methods:
- Generated mice with adipocyte-specific knockout of Raptor (mTORC1 subunit) or ATGL (lipolytic enzyme), or both.
- Characterized systemic lipid metabolism, including triglyceride and cholesterol levels, in these mouse models.
Main Results:
- Mice lacking adipocyte mTORC1 activity exhibited hypertriglyceridemia and hypercholesterolemia due to failed suppression of lipolysis.
- Inhibition of lipolysis in these mice normalized lipid levels and improved triglyceride clearance.
Conclusions:
- Unsuppressed adipose lipolysis in the fed state contributes to hyperlipidemia by impairing triglyceride clearance.
- Adipose tissue mTORC1 signaling is essential for suppressing lipolysis and maintaining systemic lipid homeostasis.
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