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Adipose-Specific Knockout of raptor Results in Lean Mice with Enhanced Mitochondrial Respiration
Open accessAbstract
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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“Knocking out the Raptor complex in adipose tissue enhances mitochondrial respiration244, but muscle-specific knockout causes muscular dystrophy in mice36.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [244]
In the citing paper
“Adipose-specific Raptor knockout mice (Raptorad−/−) have a lean phenotype and are protected against diet-induced obesity, due to enhanced energy expenditure facilitated by UCP1-mediated mitochondrial uncoupling244.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [244]
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BackgroundThe Sam68 STAR RNA-Binding Protein Regulates mTOR Alternative Splicing during Adipogenesis
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“Interestingly, adiposespecific disrupting mTORC1 signaling by knocking out Raptor prevented diet-induced obesity in mice (156).”
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“…resulting from tissuespecific knockout of raptor (mTORC1) or rictor (mTORC2) from metabolic tissues (i.e., adipose; liver; skeletal muscle) in mice align with these metabolic functions of TBK1 (Kumar et al, 2008, 2010; Polak et al, 2008; Hagiwara et al, 2012; Lee et al, 2016; Kleinert et al, 2017).”
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“In some instances conditional cell type selective knockouts had to be generated to circumvent embryonic lethality of global mouse knockouts [1–3].”
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Guridi, M., Tintignac, L. A. J., Lin, S., Kupr, B., Castets, P., & Rüegg, M. A. (2015) · Science Signaling · doi:10.1126/scisignal.aab3715 · Cited by 98
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Raptor regulates functional maturation of murine beta cells
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“Mice with reduced TOR signaling in adipose tissue show resistance to diet-induced obesity and metabolic disease.((27)) Rapamycin has also been shown to confer protection in animal and cell-based models of neurodegenerative diseases, cardiovascular disease, and against a variety of types of cancer.”
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“Conversely, the activity of mTORC1 in skeletal muscle and adipose tissue may actually promote glucose tolerance – and in the context of adipose tissue, leanness as well (Bentzinger et al., 2008; Polak et al., 2008).”
BackgroundSestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species
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Mitochondria and Organismal Longevity
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An mTORC1-Mdm2-Drosha Axis for miRNA Biogenesis in Response to Glucose- and Amino Acid-Deprivation
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“Mx1-Cre (Kühn et al., 1995), Tsc1flox/flox (Uhlmann et al., 2002), and Rptrflox/flox (Polak et al., 2008) mice were backcrossed for more than ten generations into a C57BL/6 and were treated with 400 mg polyinosinic:polycytidylic acid (pIpC, 2 mg/ml in 13 DPBS, Sigma-Aldrich) seven times every other day by intraperito…”
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“Genetic inhibition of either TOR and S6K in mice leads to alterations in metabolic activity in adipose tissue (Um et al , 2004, 2006; Polak et al , 2008; Cybulski et al , 2009).”
A novel adipose-specific gene deletion model demonstrates potential pitfalls of existing methods
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BackgroundMetabolic Communication and Healthy Aging: Where Should We Focus Our Energy?
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“Raptor mice were described previously (18).”
BackgroundmTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold
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“Moreover, deletion of raptor in adipose tissue protects mice from high fat diet induced weight gain and improves their glucose tolerance [41].”
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Targeting mTOR Signaling Can Prevent the Progression of FSGS
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BackgroundMammalian TOR signaling to the AGC kinases
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“In vivo, the adipose tissue-specific knockout (KO) of mTORC1 component raptor led to defective Thr389 phosphorylation and shared similar phenotype with germline KO of S6K, highlighting the importance of mTORC1 in S6K regulation (Polak et al., 2008).”
BackgroundLiu, W., Singh, R., Choi, C. S., Lee, H., Keramati, A. R., Samuel, V. T., Lifton, R. P., Shulman, G. I., & Mani, A. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.286724 · Cited by 78
“Association among Wnt/LRP6, mTOR activity, and UCP1 and PGC1- expression is best demonstrated in LRP6 / mice in which loss of LRP6 allele results in reduced mTOR activity, excessive expression of UCP1 and PGC1- , reduced adiposity, and insulin sensitivity.”
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“Finally, whether and how hypothalamic mTORC1 regulates the SNS outflow to BAT and WAT to regulate thermogenesis and energy expenditure are still largely unknown.”
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“Loss of the TOR effector, S6K1, prevents lipid accumulation after HFD treatment, and ablation of the TORC1 component, raptor, in adipose tissue also prevents HFD-induced obesity, which suggests that adipose is a critical site for TOR to mediate its effect [42,43].”
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Identification of Adipocyte Genes Regulated by Caloric Intake
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“In mice, adipose-specific interference of protein translation has been shown to have profound impact on obesity and insulin resistance, effects that appear to be attributed to changes in energy expenditure (16).”
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“Miceharboringfloxedallelesof Rptor (Bentzingeretal., 2008; Polak et al., 2008), mice carrying a Cre transgene under control of the Mpz promoter (RRID:IMSR_JAX:017927), or a CreERT2 transgene under controlofthe Plp1 promoterhavebeendescribed(Feltrietal.,1999;Jaegleet al., 2003; Leone et al., 2003).”
Angelicin—A Furocoumarin Compound With Vast Biological Potential
Mahendra, C. K., Tan, L. T., Lee, W.-L., Yap, W. H., Pusparajah, P., Low, L. E., Tang, S. Y., Chan, K., Lee, L., & Goh, B. H. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00366 · Cited by 74
“…p-4EBP1 was upregulated under both differentiation conditions for 7 and 14 days (Wang et al., 2017b). mTOR is a conserved pathway that plays a role in regulating cell growth and metabolism and it had been reported that mTORC1 participates in adipogenesis (Polak et al., 2008; Betz and Hall, 2013).”
BackgroundResultYAP and TAZ protect against white adipocyte cell death during obesity
Wang, L., Wang, S., Shi, Y. X., Li, R., Günther, S., Ong, Y. T., Potente, M., Yuan, Z., Liu, E., & Offermanns, S. (2020) · Nature Communications · doi:10.1038/s41467-020-19229-3 · Cited by 75
Molecular mechanisms underlying metabolic syndrome: the expanding role of the adipocyte
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Recent Progress in Engineering Mesenchymal Stem Cell Differentiation
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“Previous studies have shown the correlation of high level of BAT with weight loss and energy consumption in obese subjects [63, 64].”
Torres‐Leal, F. L., Fonseca‐Alaniz, M. H., Teodoro, G. F. R., de Capitani, M. D., Vianna, D., Pantaleão, L. C., de Matos‐Neto, E. M., Rogero, M. M., Donato, J., & Tirapegui, J. (2011) · Nutrition & Metabolism · doi:10.1186/1743-7075-8-62 · Cited by 72
Hot topics in aging research: protein translation and TOR signaling, 2010
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“Adipose-specific knockout of the TORC1 component raptor results in resistance to diet-induced obesity, as does whole-body knockout of S6K1 (Um et al., 2004; Polak et al., 2008).”
BackgroundZhang, L., Tschumi, B., Corgnac, S., Rüegg, M. A., Hall, M. N., Mach, J., Romero, P. J., & Donda, A. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400769 · Cited by 71
“Raptor mice have been described previously (24).”
Self-citationWang, Q., Sun, J., Liu, M., Zhou, Y., Zhang, L., & Li, Y. (2021) · Biomolecules · doi:10.3390/biom11121757 · Cited by 77
“In addition, it has been observed that brown adipose tissue and energy expenditure are increased, and the resistance to obesity induced by a high-fat diet is enhanced in mice with Raptor knockout in adipocytes [79].”
BackgroundQuintens, R., Singh, S., Lemaire, K., Bock, K. D., Granvik, M., Schraenen, A., Vroegrijk, I. O. C. M., Costa, V., Noten, P. V., Lambrechts, D., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056719 · Cited by 70
Early Influences of Nutrition on Postnatal Growth
Koletzko, B. V., Beyer, J., Brands, B. A., Demmelmair, H., Grote, V., Haile, G., Gruszfeld, D., Rzehak, P., Socha, P., Weber, M., et al. (2013) · Nestlé Nutrition Institute Workshop series · doi:10.1159/000342533 · Cited by 71
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Rapamycin-induced metabolic defects are reversible in both lean and obese mice
Liu, Y., Diaz, V., Fernandez, E., Strong, R., Ye, L., Baur, J. A., Lamming, D. W., Richardson, A., & Salmon, A. B. (2014) · Aging · doi:10.18632/aging.100688 · Cited by 68
“Reduced mTORC1 signaling either in adipose tissue (by adiposespecific Raptor deletion) or through genetic ablation of the mTORC1 effector S6K1 prevents high fat dietinduced metabolic dysfunction [3, 4, 35].”
BackgroundTsai, S.-Y., Rodriguez, A. A., Dastidar, S. G., Del Greco, E., Carr, K. L., Sitzmann, J. M., Academia, E. C., Viray, C. M., Martinez, L. L., Kaplowitz, B. S., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.07.029 · Cited by 63
“Reduced mTORC1 activity has been reported to prevent development of T2D and protect against diabetic nephropathy in both type I and type II diabetic mouse models (Godel et al., 2011; Inoki et al., 2011; Polak et al., 2008; Um et al., 2004; Yang et al., 2007).”
BackgroundHypothalamic mTORC2 is essential for metabolic health and longevity
Chellappa, K., Brinkman, J. A., Mukherjee, S., Morrison, M., Alotaibi, M. I., Carbajal, K. A., Alhadeff, A. L., Perron, I. J., Yao, R., Purdy, C. S., et al. (2019) · Aging Cell · doi:10.1111/acel.13014 · Cited by 62
“…muscle, is associated with disruption of glucose intolerance and insulin resis‐ tance (Bentzinger et al., 2008; Blair, Archer, & Hand, 2013; Kumar et al., 2008, 2010; Lamming, Demirkan, et al., 2014; Lamming, Mihaylova, et al., 2014; Lamming et al., 2012; Polak et al., 2008; Tang et al., 2016).”
BackgroundAdipose mTORC1 Suppresses Prostaglandin Signaling and Beige Adipogenesis via the CRTC2-COX-2 Pathway
Zhang, X., Luo, Y., Wang, C., Ding, X., Yang, X., Wu, D., Silva, F. D., Yang, Z., Zhou, Q., Wang, L., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.08.055 · Cited by 67
“Several studies agree that adipose inhibition of mTORC1 leads to browning of WAT and that overactivation of mTORC1 in adipose tissue suppresses thermogenesis and exacerbates diet-induced obesity and insulin resistance in mice (Liu et al., 2014; Polak et al., 2008; Um et al., 2004; Wada et al., 2016).”
BackgroundJayatunga, D. P. W., Hone, E., Khaira, H., Lunelli, T., Singh, H., Guillemin, G. J., Fernando, B., Garg, M. L., Verdile, G., & Martins, R. N. (2021) · Nutrients · doi:10.3390/nu13113744 · Cited by 67
“Attenuation of mTOR signalling is associated with impaired glucose metabolism [87], resulting in mitohormesis and subsequent tissue-dependent modulation of mitobiogenesis [88].”
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“phenocopying our rapamycin-treated animals [11].”
BackgroundCardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy
Shende, P., Xu, L., Morandi, C., Pentassuglia, L., Heim, P., Lebboukh, S., Berthonneche, C., Pedrazzini, T., Kaufmann, B. A., Hall, M. N., et al. (2015) · Cardiovascular Research · doi:10.1093/cvr/cvv252 · Cited by 67
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Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis
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“Among the various effectors, we find a reduction in mTORC1 activity in white, but not brown, adipocytes, which appears as the primary mediator of the observed loss in WAT mass, inflammation, and fibrosis as adipose selective raptor knockout has an almost identical phenotype in white adipose tissue [38,45].”
BackgroundThe Genetic Basis of Childhood Obesity: A Systematic Review
Vourdoumpa, A., Paltoglou, G., & Charmandari, E. (2023) · Nutrients · doi:10.3390/nu15061416 · Cited by 84
Targeting mitochondrial dysfunction as in aging and glaucoma
Osborne, N. N., Núñez‐Álvarez, C., & del Olmo‐Aguado, S. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.05.010 · Cited by 64
mTORC1 signaling in energy balance and metabolic disease
Catania, C., Binder, E., & Cota, D. (2010) · International Journal of Obesity · doi:10.1038/ijo.2010.208 · Cited by 68
The Complex Roles of Mechanistic Target of Rapamycin in Adipocytes and Beyond
Lee, P. L., Jung, S. M., & Guertin, D. A. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.01.004 · Cited by 66
Protective role of mitoquinone against impaired mitochondrial homeostasis in metabolic syndrome
Yang, J., Suo, H., & Song, J. (2020) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2020.1809344 · Cited by 65
Amino acid starvation has opposite effects on mitochondrial and cytosolic protein synthesis
Johnson, M. A., Vidoni, S., Durigon, R., Pearce, S. F., Rorbach, J., He, J., Brea-Calvo, G., Minczuk, M., Reyes, A., Holt, I. J., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093597 · Cited by 63
Hu, J. P., Nie, Y., Chen, S., Xie, C., Fan, Q., Wang, Z., Long, B., Yan, G., Zhong, Q., & Yan, X. (2017) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2017.05.026 · Cited by 64
Dai, Q., Xu, Z., Ma, X., Niu, N., Zhou, S., Xie, F., Jiang, L., Wang, J., & Zou, W. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.110 · Cited by 63
Rapamycin Reverses Metabolic Deficits in Lamin A/C-Deficient Mice
Liao, C.-Y., Anderson, S. S., Chicoine, N. H., Mayfield, J., Academia, E. C., Wilson, J. A., Pongkietisak, C., Thompson, M. A., Lagmay, E. P., Miller, D. M., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.10.040 · Cited by 62
Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion
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“Hormone content in each gate was analyzed in 4 control animals by ELISAs for glucagon (Duoset, R&D Systems) and insulin (Alpco) and We generated 3 experimental groups for all described experiments: controls (Raptorfl/fl, Raptorfl/+, and glucagon-Cre), αRaptorKO (glucagonCre; Raptorfl/fl), and αRaptorHET (glucagon-Cre;…”
BackgroundMethodInfluentialSelf-citationCastro, W., Chelbi, S. T., Niogret, C., Ramón-Barros, C., Welten, S. P. M., Osterheld, K., Wang, H., Rota, G., Morgado, L., Vivier, É., et al. (2018) · Nature Immunology · doi:10.1038/s41590-018-0144-9 · Cited by 62
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“Previous studies show that inhibition of MTORC1 by fabp4driven ablation of RPS6KB or RPTOR enhances thermogenesis and energy expenditure, leading to protection against dietinduced obesity and glucose intolerance [21,32].”
Background
Metadata
- 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.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 8
- Issue
- 5
- Pages
- 399-410
- ISSN
- 1550-4131 (ISSN-L)
- 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
- 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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