Abstract
In eukaryotic cells, the mammalian target of rapamycin complex 1 (sometimes referred to as the mechanistic target of rapamycin complex 1; mTORC1) orchestrates cellular metabolism in response to environmental energy availability. As a result, at the organismal level, mTORC1 signalling regulates the intake, storage and use of energy by acting as a hub for the actions of nutrients and hormones, such as leptin and insulin, in different cell types. It is therefore unsurprising that deregulated mTORC1 signalling is associated with obesity. Strategies that increase energy expenditure offer therapeutic promise for the treatment of obesity. Here we review current evidence illustrating the critical role of mTORC1 signalling in the regulation of energy expenditure and adaptive thermogenesis through its various effects in neuronal circuits, adipose tissue and skeletal muscle. Understanding how mTORC1 signalling in one organ and cell type affects responses in other organs and cell types could be key to developing better, safer treatments targeting this pathway in obesity.
Key points
-
Mammalian target of rapamycin complex 1 (mTORC1) plays different and complex roles in the regulation of energy expenditure.
-
mTORC1 cell-specific actions affect other cells and organs by altering cellular metabolism and the use of energy substrates while modifying inter-organ communication.
-
mTORC1 activation is required for central sympathetic nervous system (SNS) stimulation and SNS effects on white adipose tissue (WAT), brown adipose tissue (BAT) and skeletal muscle, which lead to WAT browning and increased energy expenditure.
-
mTORC1 stimulates non-shivering thermogenesis in BAT and skeletal muscle.
-
mTORC1 is a master regulator of skeletal muscle metabolism and it is crucial for skeletal muscle mass maintenance.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Brown, E. J. et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756–758 (1994).
Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S. H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35–43 (1994).
Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020).
Szwed, A., Kim, E. & Jacinto, E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol. Rev. 101, 1371–1426 (2021).
Christoffersen, B. O. et al. Beyond appetite regulation: targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss. Obesity 30, 841–857 (2022).
Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).
Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177–189 (2002).
Kim, D. H. et al. GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11, 895–904 (2003).
Fonseca, B. D., Smith, E. M., Lee, V. H., MacKintosh, C. & Proud, C. G. PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. J. Biol. Chem. 282, 24514–24524 (2007).
Vander Haar, E., Lee, S. I., Bandhakavi, S., Griffin, T. J. & Kim, D. H. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9, 316–323 (2007).
Peterson, T. R. et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137, 873–886 (2009).
Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008).
Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K. L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10, 935–945 (2008).
Sancak, Y. et al. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290–303 (2010).
Bar-Peled, L. et al. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340, 1100–1106 (2013).
Yang, H. et al. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature 552, 368–373 (2017).
Menon, S. et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156, 771–785 (2014).
Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C. & Blenis, J. Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259–1268 (2003).
Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol. 5, 578–581 (2003).
Hoxhaj, G. et al. The mTORC1 signaling network senses changes in cellular purine nucleotide levels. Cell Rep. 21, 1331–1346 (2017).
Emmanuel, N. et al. Purine nucleotide availability regulates mTORC1 activity through the Rheb GTPase. Cell Rep. 19, 2665–2680 (2017).
Um, S. H. et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200–205 (2004).
Yu, Y. et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332, 1322–1326 (2011).
Hsu, P. P. et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332, 1317–1322 (2011).
Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).
Dagon, Y. et al. p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin’s effect on food intake. Cell Metab. 16, 104–112 (2012).
Ling, N. X. Y. et al. mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress. Nat. Metab. 2, 41–49 (2020).
Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991 (2009).
Yu, L. et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942–946 (2010).
Cunningham, J. T. et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1ɑ transcriptional complex. Nature 450, 736–740 (2007).
Morita, M. et al. mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metab. 18, 698–711 (2013).
Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).
Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6, 1122–1128 (2004).
Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).
Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).
Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).
Fang, Y. et al. Duration of rapamycin treatment has differential effects on metabolism in mice. Cell Metab. 17, 456–462 (2013).
Ye, L., Varamini, B., Lamming, D. W., Sabatini, D. M. & Baur, J. A. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. Front. Genet. 3, 177 (2012).
Festuccia, W. T. et al. PPARγ activation attenuates glucose intolerance induced by mTOR inhibition with rapamycin in rats. Am. J. Physiol. Endocrinol. Metab. 306, E1046–E1054 (2014).
Houde, V. P. et al. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 59, 1338–1348 (2010).
Tran, L. T. et al. Hypothalamic control of energy expenditure and thermogenesis. Exp. Mol. Med. 54, 358–369 (2022).
Hyun, U. & Sohn, J. W. Autonomic control of energy balance and glucose homeostasis. Exp. Mol. Med. 54, 370–376 (2022).
Lee, K. Y. et al. Lessons on conditional gene targeting in mouse adipose tissue. Diabetes 62, 864–874 (2013).
Meng, W. et al. Rheb inhibits beiging of white adipose tissue via PDE4D5-dependent downregulation of the cAMP-PKA signaling pathway. Diabetes 66, 1198–1213 (2017).
Meng, W. et al. Rheb promotes brown fat thermogenesis by Notch-dependent activation of the PKA signaling pathway. J. Mol. Cell. Biol. 11, 781–790 (2019).
Muller, T. D., Klingenspor, M. & Tschop, M. H. Revisiting energy expenditure: how to correct mouse metabolic rate for body mass. Nat. Metab. 3, 1134–1136 (2021).
Hu, F., Xu, Y. & Liu, F. Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis. Am. J. Physiol. Endocrinol. Metab. 310, E994–E1002 (2016).
Cota, D. et al. Hypothalamic mTOR signaling regulates food intake. Science 312, 927–930 (2006). The first study to demonstrate that hypothalamic mTORC1 responds to hormones and nutrients and regulates feeding behaviour.
Blouet, C., Ono, H. & Schwartz, G. J. Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell Metab. 8, 459–467 (2008).
Yeo, G. S. H. et al. The melanocortin pathway and energy homeostasis: from discovery to obesity therapy. Mol. Metab. 48, 101206 (2021).
Shi, Y. C. et al. Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab. 17, 236–248 (2013).
Rothwell, N. J. & Stock, M. J. A role for insulin in the diet-induced thermogenesis of cafeteria-fed rats. Metabolism 30, 673–678 (1981).
Rossi, J. et al. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab. 13, 195–204 (2011).
Harlan, S. M., Guo, D. F., Morgan, D. A., Fernandes-Santos, C. & Rahmouni, K. Hypothalamic mTORC1 signaling controls sympathetic nerve activity and arterial pressure and mediates leptin effects. Cell Metab. 17, 599–606 (2013).
Muta, K., Morgan, D. A. & Rahmouni, K. The role of hypothalamic mTORC1 signaling in insulin regulation of food intake, body weight, and sympathetic nerve activity in male mice. Endocrinology 156, 1398–1407 (2015).
Mapps, A. A. et al. Satellite glia modulate sympathetic neuron survival, activity, and autonomic function. Elife 11, e74295 (2022).
Esler, M. et al. Mechanisms of sympathetic activation in obesity-related hypertension. Hypertension 48, 787–796 (2006).
Mori, H. et al. Critical role for hypothalamic mTOR activity in energy balance. Cell Metab. 9, 362–374 (2009).
Yang, S. B. et al. Rapamycin ameliorates age-dependent obesity associated with increased mTOR signaling in hypothalamic POMC neurons. Neuron 75, 425–436 (2012).
Smith, M. A. et al. Ribosomal S6K1 in POMC and AgRP neurons regulates glucose homeostasis but not feeding behavior in mice. Cell Rep. 11, 335–343 (2015).
Burke, L. K. et al. mTORC1 in AGRP neurons integrates exteroceptive and interoceptive food-related cues in the modulation of adaptive energy expenditure in mice. Elife 6, e22848 (2017). An elegant study showing that bidirectional modulation of mTORC1 signalling in hypothalamic AgRP neurons controls energy expenditure.
Haissaguerre, M. et al. mTORC1-dependent increase in oxidative metabolism in POMC neurons regulates food intake and action of leptin. Mol. Metab. 12, 98–106 (2018).
Mazier, W. et al. mTORC1 and CB1 receptor signaling regulate excitatory glutamatergic inputs onto the hypothalamic paraventricular nucleus in response to energy availability. Mol. Metab. 28, 151–159 (2019).
Saucisse, N. et al. Functional heterogeneity of POMC neurons relies on mTORC1 signaling. Cell Rep. 37, 109800 (2021).
Ma, Y. et al. Neuronal miR-29a protects from obesity in adult mice. Mol. Metab. 61, 101507 (2022).
Carnevalli, L. S. et al. S6K1 plays a critical role in early adipocyte differentiation. Dev. Cell 18, 763–774 (2010).
Labbe, S. M. et al. mTORC1 is required for brown adipose tissue recruitment and metabolic adaptation to cold. Sci. Rep. 6, 37223 (2016). This study shows that cold activates mTORC1 in the BAT in a sympathetic nervous system-dependent fashion. This is, in turn, necessary for cold-induced BAT expansion, mitochondrial biogenesis and oxidative metabolism.
Lee, P. L., Tang, Y., Li, H. & Guertin, D. A. Raptor/mTORC1 loss in adipocytes causes progressive lipodystrophy and fatty liver disease. Mol. Metab. 5, 422–432 (2016). This study describes the crucial role of mTORC1 in white adipose tissue expansion and maintenance, which is critical for systemic metabolic homeostasis.
Chimin, P. et al. Adipocyte mTORC1 deficiency promotes adipose tissue inflammation and NLRP3 inflammasome activation via oxidative stress and de novo ceramide synthesis. J. Lipid Res. 58, 1797–1807 (2017).
Lee, P. L., Jung, S. M. & Guertin, D. A. The complex roles of mechanistic target of rapamycin in adipocytes and beyond. Trends Endocrinol. Metab. 28, 319–339 (2017).
Liu, D. et al. Activation of mTORC1 is essential for β-adrenergic stimulation of adipose browning. J. Clin. Invest. 126, 1704–1716 (2016). This study shows that β-adrenergic receptor signalling recruits mTORC1 in adipocytes to induce adipose tissue browning.
Sakers, A., De Siqueira, M. K., Seale, P. & Villanueva, C. J. Adipose-tissue plasticity in health and disease. Cell 185, 419–446 (2022).
Valdivia, L. F. G. et al. Cold acclimation and pioglitazone combined increase thermogenic capacity of brown and white adipose tissues but this does not translate into higher energy expenditure in mice. Am. J. Physiol. Endocrinol. Metab. 324, E358–E373 (2023).
von Essen, G. et al. Highly recruited brown adipose tissue does not in itself protect against obesity. Mol. Metab. 76, 101782 (2023).
Tran, C. M. et al. Rapamycin blocks induction of the thermogenic program in white adipose tissue. Diabetes 65, 927–941 (2016).
Le, T. D. V. et al. Glucagon-like peptide-1 receptor activation stimulates PKA-mediated phosphorylation of raptor and this contributes to the weight loss effect of liraglutide. Elife 12, e80944 (2023).
Hostrup, M. & Onslev, J. The beta2-adrenergic receptor–a re-emerging target to combat obesity and induce leanness? J. Physiol. 600, 1209–1227 (2022).
Jessen, S. et al. Beta2-adrenergic agonist clenbuterol increases energy expenditure and fat oxidation, and induces mTOR phosphorylation in skeletal muscle of young healthy men. Drug. Test. Anal. 12, 610–618 (2020).
Magdalon, J. et al. Constitutive adipocyte mTORC1 activation enhances mitochondrial activity and reduces visceral adiposity in mice. Biochim. Biophys. Acta 1861, 430–438 (2016).
Zhang, X. et al. Adipose mTORC1 suppresses prostaglandin signaling and beige adipogenesis via the CRTC2-COX-2 pathway. Cell Rep. 24, 3180–3193 (2018).
Xu, Y. et al. Asparagine reinforces mTORC1 signaling to boost thermogenesis and glycolysis in adipose tissues. EMBO J. 40, e108069 (2021).
Olsen, J. M. et al. Glucose uptake in brown fat cells is dependent on mTOR complex 2-promoted GLUT1 translocation. J. Cell Biol. 207, 365–374 (2014).
Albert, V. et al. mTORC2 sustains thermogenesis via Akt-induced glucose uptake and glycolysis in brown adipose tissue. EMBO Mol. Med. 8, 232–246 (2016).
Castro, E. et al. Adipocyte-specific mTORC2 deficiency impairs BAT and iWAT thermogenic capacity without affecting glucose uptake and energy expenditure in cold-acclimated mice. Am. J. Physiol. Endocrinol. Metab. 321, E592–E605 (2021).
Liebscher, G. et al. The lysosomal LAMTOR/ragulator complex is essential for nutrient homeostasis in brown adipose tissue. Mol. Metab. 71, 101705 (2023).
Liu, M. et al. Grb10 promotes lipolysis and thermogenesis by phosphorylation-dependent feedback inhibition of mTORC1. Cell Metab. 19, 967–980 (2014).
Liu, F. & Roth, R. A. Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function. Proc. Natl Acad. Sci. USA 92, 10287–10291 (1995).
Liu, H. et al. Hypothalamic Grb10 enhances leptin signalling and promotes weight loss. Nat. Metab. 5, 147–164 (2023).
Holt, L. J. & Siddle, K. Grb10 and Grb14: enigmatic regulators of insulin action–and more? Biochem. J. 388, 393–406 (2005).
Li, H., Wang, C., Li, L. & Li, L. Skeletal muscle non-shivering thermogenesis as an attractive strategy to combat obesity. Life Sci. 269, 119024 (2021).
Guridi, M. et al. Activation of mTORC1 in skeletal muscle regulates whole-body metabolism through FGF21. Sci. Signal. 8, ra113 (2015).
Guridi, M. et al. Alterations to mTORC1 signaling in the skeletal muscle differentially affect whole-body metabolism. Skelet. Muscle 6, 13 (2016). This study provides a direct comparison of the metabolic effects driven by either genetic mTORC1 overactivation or inhibition in skeletal muscle.
Blondin, D. P. & Haman, F. Shivering and nonshivering thermogenesis in skeletal muscles. Handb. Clin. Neurol. 156, 153–173 (2018).
Bal, N. C. et al. Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat. Med. 18, 1575–1579 (2012). A noteworthy study describing the necessary role of sarcolipin in muscle-based non-shivering thermogenesis.
Pant, M., Bal, N. C. & Periasamy, M. Sarcolipin: a key thermogenic and metabolic regulator in skeletal muscle. Trends Endocrinol. Metab. 27, 881–892 (2016).
Chambers, P. J., Juracic, E. S., Fajardo, V. A. & Tupling, A. R. Role of SERCA and sarcolipin in adaptive muscle remodeling. Am. J. Physiol. Cell. Physiol. 322, C382–C394 (2022).
Tao, R. et al. Hepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance. Mol. Metab. 71, 101703 (2023). This article illustrates the relationship between genetic mTORC1 overactivity in muscle and sarcolipin–SERCA-mediated non-shivering thermogenesis, which protects against obesity.
Lopez, R. J. et al. Raptor ablation in skeletal muscle decreases Cav1.1 expression and affects the function of the excitation-contraction coupling supramolecular complex. Biochem. J. 466, 123–135 (2015).
Baraldo, M. et al. Inducible deletion of raptor and mTOR from adult skeletal muscle impairs muscle contractility and relaxation. J. Physiol. 600, 5055–5075 (2022).
Bentzinger, C. F. et al. Differential response of skeletal muscles to mTORC1 signaling during atrophy and hypertrophy. Skelet. Muscle 3, 6 (2013).
Dutchak, P. A. et al. Loss of a negative regulator of mTORC1 induces aerobic glycolysis and altered fiber composition in skeletal muscle. Cell Rep. 23, 1907–1914 (2018).
Crombie, E. M. et al. Activation of eIF4E-binding-protein-1 rescues mTORC1-induced sarcopenia by expanding lysosomal degradation capacity. J. Cachexia Sarcopenia Muscle 14, 198–213 (2023).
Tang, H. et al. mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism. Aging Cell 18, e12943 (2019).
Romanino, K. et al. Myopathy caused by mammalian target of rapamycin complex 1 (mTORC1) inactivation is not reversed by restoring mitochondrial function. Proc. Natl Acad. Sci. USA 108, 20808–20813 (2011).
Tinline-Goodfellow, C. T., Lees, M. J. & Hodson, N. The skeletal muscle fiber periphery: a nexus of mTOR-related anabolism. Sports Med. Health Sci. 5, 10–19 (2023).
D’Hulst, G., Masschelein, E. & De Bock, K. Resistance exercise enhances long-term mTORC1 sensitivity to leucine. Mol. Metab. 66, 101615 (2022).
Yamaoka, I. et al. Insulin mediates the linkage acceleration of muscle protein synthesis, thermogenesis, and heat storage by amino acids. Biochem. Biophys. Res. Commun. 386, 252–256 (2009).
Westerterp, K. R., Wilson, S. A. & Rolland, V. Diet induced thermogenesis measured over 24 h in a respiration chamber: effect of diet composition. Int. J. Obes. Relat. Metab. Disord. 23, 287–292 (1999).
Izumiya, Y. et al. Fast/glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab. 7, 159–172 (2008).
You, J. S. et al. The role of raptor in the mechanical load-induced regulation of mTOR signaling, protein synthesis, and skeletal muscle hypertrophy. FASEB J. 33, 4021–4034 (2019).
Khan, N. A. et al. mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression. Cell Metab. 26, 419–428.e5 (2017).
Yasuda, T., Ishihara, T., Ichimura, A. & Ishihara, N. Mitochondrial dynamics define muscle fiber type by modulating cellular metabolic pathways. Cell Rep. 42, 112434 (2023).
Keipert, S. et al. Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. Am. J. Physiol. Endocrinol. Metab. 306, E469–E482 (2014).
Tezze, C. et al. Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab. 25, 1374–1389.e6 (2017).
Ost, M. et al. Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress. EMBO Rep. 21, e48804 (2020).
Porflitt-Rodriguez, M. et al. Effects of aerobic exercise on fibroblast growth factor 21 in overweight and obesity. A systematic review. Metabolism 129, 155137 (2022).
Klein, A. B., Kleinert, M., Richter, E. A. & Clemmensen, C. GDF15 in appetite and exercise: essential player or coincidental bystander? Endocrinology 163, bqab242 (2022).
Wang, D. et al. GDF15 promotes weight loss by enhancing energy expenditure in muscle. Nature 619, 143–150 (2023). A remarkable study deciphering how GDF15 promotes energy expenditure and weight loss by enhancing adrenergic signalling in skeletal muscle.
Khamzina, L., Veilleux, A., Bergeron, S. & Marette, A. Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology 146, 1473–1481 (2005).
Polak, P. et al. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab. 8, 399–410 (2008).
Bodur, C. et al. TBK1-mTOR signaling attenuates obesity-linked hyperglycemia and insulin resistance. Diabetes 71, 2297–2312 (2022).
Scarpace, P. J. et al. Rapamycin normalizes serum leptin by alleviating obesity and reducing leptin synthesis in aged rats. J. Gerontol. A. Biol. Sci. Med. Sci. 71, 891–899 (2016).
Spinelli, R. et al. Increased cell senescence in human metabolic disorders. J. Clin. Invest. 133, e169922 (2023).
Mannick, J. B. & Lamming, D. W. Targeting the biology of aging with mTOR inhibitors. Nat. Aging 3, 642–660 (2023).
Mahoney, S. J. et al. A small molecule inhibitor of Rheb selectively targets mTORC1 signaling. Nat. Commun. 9, 548 (2018).
Schreiber, K. H. et al. A novel rapamycin analog is highly selective for mTORC1 in vivo. Nat. Commun. 10, 3194 (2019).
Zhang, Z. et al. Brain-restricted mTOR inhibition with binary pharmacology. Nature 609, 822–828 (2022).
Tschop, M. H. et al. A guide to analysis of mouse energy metabolism. Nat. Methods 9, 57–63 (2011).
Martin, A., Fox, D., Murphy, C. A., Hofmann, H. & Koehler, K. Tissue losses and metabolic adaptations both contribute to the reduction in resting metabolic rate following weight loss. Int. J. Obes. 46, 1168–1175 (2022).
Saito, M., Matsushita, M., Yoneshiro, T. & Okamatsu-Ogura, Y. Brown adipose tissue, diet-induced thermogenesis, and thermogenic food ingredients: from mice to men. Front. Endocrinol. 11, 222 (2020).
She, Q. Y. et al. Fibroblast growth factor 21: a “rheostat” for metabolic regulation? Metabolism 130, 155166 (2022).
Klein Hazebroek, M. & Keipert, S. Adapting to the cold: a role for endogenous fibroblast growth factor 21 in thermoregulation? Front. Endocrinol. 11, 389 (2020).
Potthoff, M. J. et al. FGF21 induces PGC-1ɑ and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc. Natl Acad. Sci. USA 106, 10853–10858 (2009).
Breit, S. N. et al. GDF15 enhances body weight and adiposity reduction in obese mice by leveraging the leptin pathway. Cell Metab. 35, 1341–1355.e3 (2023).
Zhang, S. Y. et al. Metformin triggers a kidney GDF15-dependent area postrema axis to regulate food intake and body weight. Cell Metab. 35, 875–886.e5 (2023).
Day, E. A. et al. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat. Metab. 1, 1202–1208 (2019).
Klein, A. B. et al. The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. Cell Rep. 40, 111258 (2022).
Benichou, O. et al. Discovery, development, and clinical proof of mechanism of LY3463251, a long-acting GDF15 receptor agonist. Cell Metab. 35, 274–286.e10 (2023).
Weichhart, T., Hengstschlager, M. & Linke, M. Regulation of innate immune cell function by mTOR. Nat. Rev. Immunol. 15, 599–614 (2015).
Matarese, G. The link between obesity and autoimmunity. Science 379, 1298–1300 (2023).
Jiang, H., Westerterp, M., Wang, C., Zhu, Y. & Ai, D. Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice. Diabetologia 57, 2393–2404 (2014).
Ying, L. et al. Macrophage LAMTOR1 deficiency prevents dietary obesity and insulin resistance through inflammation-induced energy expenditure. Front. Cell. Dev. Biol. 9, 672032 (2021).
Kalin, S. et al. A Stat6/Pten axis links regulatory T cells with adipose tissue function. Cell Metab. 26, 475–492.e7 (2017).
Acknowledgements
The authors acknowledge funding from INSERM (to D.C.), Agence Nationale de la Recherche (ANR-18-CE14-0029, ANR-21-CE14-0018 and ANR-22-CE14-0016, to D.C.), University of Bordeaux’s IdEx ‘Investments for the Future’ program/GPR BRAIN_2030 (to D.C.) and the Fondation pour la Recherche Médicale (FRM-EQU202303016291, to D.C.; FRM-ARF201809006962, to C.A.; FRM-SPF202004011774, to C.M.; and FRM-SPF202209015803, to A.J.L.-G.).
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Endocrinology thanks William Festuccia and Mitsugu Shimobayashi for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Allard, C., Miralpeix, C., López-Gambero, A.J. et al. mTORC1 in energy expenditure: consequences for obesity. Nat Rev Endocrinol 20, 239–251 (2024). https://doi.org/10.1038/s41574-023-00934-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41574-023-00934-0
