mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia

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 (...

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Main Authors:	Lauren M. Paolella, Sarmistha Mukherjee, Cassie M. Tran, Bruna Bellaver, Mindy Hugo, Timothy S. Luongo, Swapnil V. Shewale, Wenyun Lu, Karthikeyani Chellappa, Joseph A. Baur
Format:	Article
Language:	English
Published:	Elsevier 2020-02-01
Series:	Molecular Metabolism
Online Access:	http://www.sciencedirect.com/science/article/pii/S2212877819309548

id	doaj-b5faee1960844042ab6ab3295bfd6258
record_format	Article
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Lauren M. Paolella Sarmistha Mukherjee Cassie M. Tran Bruna Bellaver Mindy Hugo Timothy S. Luongo Swapnil V. Shewale Wenyun Lu Karthikeyani Chellappa Joseph A. Baur
spellingShingle	Lauren M. Paolella Sarmistha Mukherjee Cassie M. Tran Bruna Bellaver Mindy Hugo Timothy S. Luongo Swapnil V. Shewale Wenyun Lu Karthikeyani Chellappa Joseph A. Baur mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia Molecular Metabolism
author_facet	Lauren M. Paolella Sarmistha Mukherjee Cassie M. Tran Bruna Bellaver Mindy Hugo Timothy S. Luongo Swapnil V. Shewale Wenyun Lu Karthikeyani Chellappa Joseph A. Baur
author_sort	Lauren M. Paolella
title	mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia
title_short	mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia
title_full	mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia
title_fullStr	mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia
title_full_unstemmed	mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia
title_sort	mtorc1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia
publisher	Elsevier
series	Molecular Metabolism
issn	2212-8778
publishDate	2020-02-01
description	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. Keywords: mTORC1, Adipose tissue, Lipolysis, Triglycerides, Rapamycin
url	http://www.sciencedirect.com/science/article/pii/S2212877819309548
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spelling	doaj-b5faee1960844042ab6ab3295bfd62582020-11-25T03:48:44ZengElsevierMolecular Metabolism2212-87782020-02-0132136147mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemiaLauren M. Paolella0Sarmistha Mukherjee1Cassie M. Tran2Bruna Bellaver3Mindy Hugo4Timothy S. Luongo5Swapnil V. Shewale6Wenyun Lu7Karthikeyani Chellappa8Joseph A. Baur9Department 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, USADepartment of Physiology, 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, USADepartment of Physiology, 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, USAInstitute for Diabetes, Obesity, and Metabolism, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Programa de Pós-graduação em Ciência Biológicas-Bioquímica, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilDepartment 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, USADepartment of Physiology, 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, USAPenn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USALewis-Sigler Institute for Integrative Genomics, Department of Chemistry, Princeton University, Princeton, NJ, 08544, USADepartment of Physiology, 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, USADepartment 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; Corresponding author. Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, 12-114 Smilow Center for Translational Research, 3400 Civic Center Boulevard, 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. Keywords: mTORC1, Adipose tissue, Lipolysis, Triglycerides, Rapamycinhttp://www.sciencedirect.com/science/article/pii/S2212877819309548

mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia

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