Cited by 480Adipose Tissue and MetabolismAdipokines, Inflammation, and Metabolic DiseasesMetabolism, Diabetes, and Cancer

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Adipose-Specific Knockout of raptor Results in Lean Mice with Enhanced Mitochondrial Respiration

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Polak, Pazit, Cybulski, Nadine, Feige, Jerome N., Auwerx, Johan, Rüegg, Markus A., Hall, Michael N.·2008·Cell Metabolism

DOI 10.1016/j.cmet.2008.09.003

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Abstract

raptor is a specific and essential component of mammalian TOR complex 1 (mTORC1), a key regulator of cell growth and metabolism. To investigate a role of adipose mTORC1 in regulation of adipose and whole-body metabolism, we generated mice with an adipose-specific knockout of raptor (raptor(ad-/-)). Compared to control littermates, raptor(ad-/-) mice had substantially less adipose tissue, were protected against diet-induced obesity and hypercholesterolemia, and exhibited improved insulin sensitivity. Leanness was in spite of reduced physical activity and unaffected caloric intake, lipolysis, and absorption of lipids from the food. White adipose tissue of raptor(ad-/-) mice displayed enhanced expression of genes encoding mitochondrial uncoupling proteins characteristic of brown fat. Leanness of the raptor(ad-/-) mice was attributed to elevated energy expenditure due to mitochondrial uncoupling. These results suggest that adipose mTORC1 is a regulator of adipose metabolism and, thereby, controls whole-body energy homeostasis.

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Background
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BackgroundSelf-citation
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Background
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Background
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Background
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Background
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“phenotype of global S6k1 knockout mice [28].”
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Background
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Result
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Background
Ginsenoside Rg1 inhibits dietary-induced obesity and improves obesity-related glucose metabolic disorders
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“mice exhibited the phenotype of resistance to dietaryinduced obesity (31).”
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Possible Biochemical Processes Underlying the Positive Health Effects of Plant-Based Diets—A Narrative Review
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Alterations to mTORC1 signaling in the skeletal muscle differentially affect whole-body metabolism
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BackgroundSelf-citation
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“Loss of raptor in fat led to browning of WAT (Polak et al. 2008).”
Background
NQO1 protects obese mice through improvements in glucose and lipid metabolism
Francesco, A. D., Choi, Y., Bernier, M., Zhang, Y., Díaz‐Ruiz, A., Aon, M. A., Kalafut, K. C., Ehrlich, M. R., Murt, K. N., Ali, A., et al. (2020) · npj Aging and Mechanisms of Disease · doi:10.1038/s41514-020-00051-6 · Cited by 40
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“In addition, fat-specific knockout (with aP2-Cre) of raptor enhances UCP1 expression and energy expenditure (16).”
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Loss of mTOR signaling affects cone function, cone structure and expression of cone specific proteins without affecting cone survival
Ma, S., Venkatesh, A., Langellotto, F., Le, Y. Z., Hall, M. N., Rüegg, M. A., & Punzo, C. (2015) · Experimental Eye Research · doi:10.1016/j.exer.2015.04.006 · Cited by 36
“Tissues with a high metabolic rate, high protein synthesis rate or a high cell division rate are generally quite affected by loss of Raptor (Cloetta et al., 2013; Polak et al., 2008; Shende et al., 2011).”
Self-citation
Mammalian target of rapamycin is essential for cardiomyocyte survival and heart development in mice
Zhang, P., Shan, T., Liang, X., Deng, C., & Kuang, S. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.08.046 · Cited by 35
“mTORC2 regulates cell growth and survival, actin cytoskeleton reorganization, protein synthesis and maturation, and metabolism via AKT and PKC-α pathway [9,10].”
Background
Regulation of Adipocyte and Macrophage Functions by mTORC1 and 2 in Metabolic Diseases
Festuccia, W. T. (2020) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201900768 · Cited by 35
Nutrigenetics and Nutrigenomics of Caloric Restriction
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“Here we show that hermes induces similar metabolic changes and mTOR signaling. mTOR signaling is a key nutrient sensing pathway, and increased activation of mTOR has been linked to insulin resistance and type 2 diabetes (Polak et al., 2008; Um et al., 2004).”
Background
Feast and famine: Adipose tissue adaptations for healthy aging
Lettieri‐Barbato, D., & Aquilano, K. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.05.007 · Cited by 35
“As consequence they have less adipose tissue, are resistant to weight gain even on a high-fat diet, and display improved metabolic parameters that could lead to life extension (Polak et al., 2008).”
Background
Molecular Basis of White Adipose Tissue Remodeling That Precedes and Coincides With Hibernation in the Syrian Hamster, a Food-Storing Hibernator
Chayama, Y., Ando, L., Sato, Y., Shigenobu, S., Anegawa, D., Fujimoto, T., Hiroki, T., Tamura, Y., Miura, M., & Yamaguchi, Y. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2018.01973 · Cited by 34
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“(25) reported that adipocyte-specific mTOR-knockout or raptor-knockout decreased the weight of WATs and induced WAT-browning.”
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Inducible raptor and rictor Knockout Mouse Embryonic Fibroblasts
Cybulski, N., Zinzalla, V., & Hall, M. N. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-430-8_16 · Cited by 34
Self-citation
Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat
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“Deletion of the adipocyte-specific mTORC1 protein Raptor results in mice that are lean and insulin sensitive with enhanced fatty acid oxidation (Polak et al., 2008); likewise, whole-body deletion of S6K1, the downstream substrate of mTORC1, improves insulin sensitivity and extends lifespan in mice…”
Influential
mTORC1 in energy expenditure: consequences for obesity
Allard, C., Miralpeix, C., López-Gambero, A. J., & Cota, D. (2024) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00934-0 · Cited by 39
“Obesity is characterized by sustained mTORC1 activity in peripheral organs, such as adipose tissue, the liver and the muscle 119,120 .”
Metabolic Regulation, Mitochondria and the Life-Prolonging Effect of Rapamycin: A Mini-Review
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Adrenoceptors promote glucose uptake into adipocytes and muscle by an insulin-independent signaling pathway involving mechanistic target of rapamycin complex 2
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mTOR and Tumor Cachexia
Duval, A. P., Jeanneret, C., Santoro, T., & Dormond, O. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082225 · Cited by 37
“Likewise, the potential of raptor null mouse embryonic fibroblasts to differentiate into adipocytes is impaired [122].”
Background
Regulation of mTOR Signaling: Emerging Role of Cyclic Nucleotide-Dependent Protein Kinases and Implications for Cardiometabolic Disease
Shi, F., & Collins, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411497 · Cited by 34
“Polak and colleagues reported that adipose-specific Raptor knockout mice had substantially less adipose tissue, elevated energy expenditure proposed to be due to mitochondrial uncoupling, were protected against diet-induced obesity, hypercholesterolemia, and insulin resistance [74].”
Background
A clerodane diterpene inhibit adipogenesis by cell cycle arrest and ameliorate obesity in C57BL/6 mice
Beg, M., Shankar, K., Varshney, S., Rajan, S., Singh, S. P., Jagdale, P. R., Puri, A., Chaudhari, B. P., Sashidhara, K. V., & Gaikwad, A. N. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.09.024 · Cited by 32
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Nesfatin-1 promotes brown adipocyte phenotype
Wang, Y., Li, Z., Zhang, X., Xiang, X., Li, Y., Mulholland, M. W., & Zhang, W. (2016) · Scientific Reports · doi:10.1038/srep34747 · Cited by 31
Quercetin improves oxidative stress-induced pancreatic beta cell alterations via mTOR-signaling
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Branched‐Chain Amino Acids and Mitochondrial Biogenesis: An Overview and Mechanistic Summary
Hinkle, J. S., Rivera, C. N., & Vaughan, R. A. (2022) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202200109 · Cited by 31
Egr1 mediates the effect of insulin on leptin transcription in adipocytes
Mohtar, O., Ozdemir, C., Roy, D., Shantaram, D., Emili, A., & Kandror, K. V. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ac119.007855 · Cited by 32
Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation
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Dictyostelium, a microbial model for brain disease
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Background
mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia
Paolella, L. M., Mukherjee, S., Tran, C. M., Bellaver, B., Hugo, M., Luongo, T. S., Shewale, S. V., Lu, W., Chellappa, K., & Baur, J. A. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.12.003 · Cited by 33
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Fisetin Suppresses Lipid Accumulation in Mouse Adipocytic 3T3-L1 Cells by Repressing GLUT4-Mediated Glucose Uptake through Inhibition of mTOR-C/EBPα Signaling
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Targeting mTOR Signaling by Dietary Polyphenols in Obesity Prevention
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Authors: Polak, P., Cybulski, N., Feige, J. N., Auwerx, J., Rüegg, M. A., & Hall, M. N.
Affiliations: University of Basel (CH)
Centre National de la Recherche Scientifique (FR)
Corresponding author: Hall, Michael N.
ORCID: Polak, Pazit
Auwerx, Johan
Rüegg, Markus A.
Hall, Michael N.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2008-11
Volume: 8
Issue: 5
Pages: 399-410
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2008.09.003
OpenAlex: W2124802842
Cited by: 480
References: 71
Citations by year: 2026: 3 · 2025: 13 · 2024: 17 · 2023: 12 · 2022: 21 · 2021: 23 · 2020: 31 · 2019: 23 · 2018: 26 · 2017: 46 · 2016: 32 · 2015: 35 · 2014: 43 · 2013: 37 · 2012: 38
FWCI: 17.61
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1719 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
edoc (University of Basel) (acceptedVersion)
HAL (submittedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
edoc (University of Basel)
Funders: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Topics: Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: raptors, mTORC1, white adipose tissue, mitochondrial uncoupling, brown adipose tissue, energy expenditure, diet-induced obesity, hypercholesterolemia, insulin sensitivity
MeSH terms: Mechanistic Target of Rapamycin Complex 1, Regulatory-Associated Protein of mTOR, Animals, Adipose Tissue, Brown, Carrier Proteins, Dietary Fats, Energy Metabolism, Hypercholesterolemia, Insulin, Male, Mitochondria, Obesity, Organ Specificity, Proteins, Transcription Factors, Mice, Knockout, Cell Respiration, Sirolimus, 3T3-L1 Cells, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Mice, Adipose Tissue, White, TOR Serine-Threonine Kinases

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Adipose-Specific Knockout of raptor Results in Lean Mice with Enhanced Mitochondrial Respiration

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