Skip to main content
Erschienen in: Diabetologia 9/2016

13.06.2016 | Article

Adipocyte-specific deletion of mTOR inhibits adipose tissue development and causes insulin resistance in mice

verfasst von: Tizhong Shan, Pengpeng Zhang, Qinyang Jiang, Yan Xiong, Yizhen Wang, Shihuan Kuang

Erschienen in: Diabetologia | Ausgabe 9/2016

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

The in vivo role of mechanistic target of rapamycin (mTOR) in the development and function of adipose tissue, especially brown adipose tissue (BAT), is not well understood. Here, we aimed to assess the effect of mTOR (also known as Mtor) knockout on adipose tissues and systemic energy metabolism.

Methods

We generated adipocyte-specific mTOR-knockout mice (Adipoq-mTOR) by crossing adiponectin-Cre (Adipoq-Cre) mice with mTOR flox/flox mice. The mice were then subjected to morphological, physiological (indirect calorimetry, glucose and insulin tolerance tests) and gene expression analyses to determine the role of mTOR in adipose tissues.

Results

We provide in vivo evidence that mTOR is essential for adipose tissue development and growth. Deletion of mTOR decreased the mass of both BAT and white adipose tissues (WAT) and induced browning of WAT. In addition, ablation of mTOR in adipose tissues caused insulin resistance and fatty liver in the Adipoq-mTOR mice. Furthermore, mTOR was required for adipocyte differentiation in vivo and activation of PPARγ ameliorated the differentiation deficiency of the mTOR-null adipocytes.

Conclusions/interpretation

Our findings demonstrate that mTOR is a critical regulator of adipogenesis and systemic energy metabolism. Our study provides key insights into the role of mTOR in adipose tissues; such knowledge may facilitate the development of novel strategies with which to treat obesity and related metabolic diseases.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359CrossRefPubMed Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359CrossRefPubMed
2.
Zurück zum Zitat Walden TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J (2012) Recruited vs. nonrecruited molecular signatures of brown, ʻbriteʼ, and white adipose tissues. Am J Physiol Endocrinol Metab 302:E19–E31CrossRefPubMed Walden TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J (2012) Recruited vs. nonrecruited molecular signatures of brown, ʻbriteʼ, and white adipose tissues. Am J Physiol Endocrinol Metab 302:E19–E31CrossRefPubMed
3.
Zurück zum Zitat Bostrom P, Wu J, Jedrychowski MP et al (2012) A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481:463–468CrossRefPubMedPubMedCentral Bostrom P, Wu J, Jedrychowski MP et al (2012) A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481:463–468CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Cao L, Choi EY, Liu XL et al (2011) White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis. Cell Metab 14:324–338CrossRefPubMedPubMedCentral Cao L, Choi EY, Liu XL et al (2011) White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis. Cell Metab 14:324–338CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Fisher FM, Kleiner S, Douris N et al (2012) FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 26:271–281CrossRefPubMedPubMedCentral Fisher FM, Kleiner S, Douris N et al (2012) FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 26:271–281CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat Ohno H, Shinoda K, Spiegelman BM, Kajimura S (2012) PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab 15:395–404CrossRefPubMedPubMedCentral Ohno H, Shinoda K, Spiegelman BM, Kajimura S (2012) PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab 15:395–404CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Bi P, Shan T, Liu W et al (2014) Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity. Nat Med 20:911–918CrossRefPubMedPubMedCentral Bi P, Shan T, Liu W et al (2014) Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity. Nat Med 20:911–918CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat Crane JD, Palanivel R, Mottillo EP et al (2015) Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nat Med 21:166–172CrossRefPubMed Crane JD, Palanivel R, Mottillo EP et al (2015) Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nat Med 21:166–172CrossRefPubMed
10.
Zurück zum Zitat Lamming DW, Sabatini DM (2013) A central role for mTOR in lipid homeostasis. Cell Metab 18:465–469CrossRefPubMed Lamming DW, Sabatini DM (2013) A central role for mTOR in lipid homeostasis. Cell Metab 18:465–469CrossRefPubMed
12.
Zurück zum Zitat Yoon MS, Zhang C, Sun Y, Schoenherr CJ, Chen J (2013) Mechanistic target of rapamycin controls homeostasis of adipogenesis. J Lipid Res 54:2166–2173CrossRefPubMedPubMedCentral Yoon MS, Zhang C, Sun Y, Schoenherr CJ, Chen J (2013) Mechanistic target of rapamycin controls homeostasis of adipogenesis. J Lipid Res 54:2166–2173CrossRefPubMedPubMedCentral
13.
14.
Zurück zum Zitat Soukas AA, Kane EA, Carr CE, Melo JA, Ruvkun G (2009) Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev 23:496–511CrossRefPubMedPubMedCentral Soukas AA, Kane EA, Carr CE, Melo JA, Ruvkun G (2009) Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev 23:496–511CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Hung CM, Calejman CM, Sanchez-Gurmaches J et al (2014) Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease. Cell Rep 8:256–271CrossRefPubMedPubMedCentral Hung CM, Calejman CM, Sanchez-Gurmaches J et al (2014) Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease. Cell Rep 8:256–271CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Olsen JM, Sato M, Dallner OS et al (2014) Glucose uptake in brown fat cells is dependent on mTOR complex 2-promoted GLUT1 translocation. J Cell Biol 207:365–374CrossRefPubMedPubMedCentral Olsen JM, Sato M, Dallner OS et al (2014) Glucose uptake in brown fat cells is dependent on mTOR complex 2-promoted GLUT1 translocation. J Cell Biol 207:365–374CrossRefPubMedPubMedCentral
17.
Zurück zum Zitat Kumar A, Lawrence JC, Jung DY et al (2010) Fat cell-specific ablation of Rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 59:1397–1406CrossRefPubMedPubMedCentral Kumar A, Lawrence JC, Jung DY et al (2010) Fat cell-specific ablation of Rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 59:1397–1406CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat El-Chaar D, Gagnon A, Sorisky A (2004) Inhibition of insulin signaling and adipogenesis by rapamycin: effect on phosphorylation of p70 S6 kinase vs eIF4E-BP1. Int J Obes 28:191–198CrossRef El-Chaar D, Gagnon A, Sorisky A (2004) Inhibition of insulin signaling and adipogenesis by rapamycin: effect on phosphorylation of p70 S6 kinase vs eIF4E-BP1. Int J Obes 28:191–198CrossRef
19.
Zurück zum Zitat Bell A, Grunder L, Sorisky A (2000) Rapamycin inhibits human adipocyte differentiation in primary culture. Obes Res 8:249–254CrossRefPubMed Bell A, Grunder L, Sorisky A (2000) Rapamycin inhibits human adipocyte differentiation in primary culture. Obes Res 8:249–254CrossRefPubMed
20.
Zurück zum Zitat Yeh WC, Bierer BE, Mcknight SL (1995) Rapamycin inhibits clonal expansion and adipogenic differentiation of 3t3-L1 cells. Proc Natl Acad Sci U S A 92:11086–11090CrossRefPubMedPubMedCentral Yeh WC, Bierer BE, Mcknight SL (1995) Rapamycin inhibits clonal expansion and adipogenic differentiation of 3t3-L1 cells. Proc Natl Acad Sci U S A 92:11086–11090CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Vila-Bedmar R, Lorenzo M, Fernandez-Veledo S (2010) Adenosine 5′-monophosphate-activated protein kinase-mammalian target of rapamycin cross talk regulates brown adipocyte differentiation. Endocrinology 151:980–992CrossRefPubMed Vila-Bedmar R, Lorenzo M, Fernandez-Veledo S (2010) Adenosine 5′-monophosphate-activated protein kinase-mammalian target of rapamycin cross talk regulates brown adipocyte differentiation. Endocrinology 151:980–992CrossRefPubMed
22.
Zurück zum Zitat Chang GR, Chiu YS, Wu YY et al (2009) Rapamycin protects against high fat diet-induced obesity in C57BL/6J mice. J Pharmacol Sci 109:496–503CrossRefPubMed Chang GR, Chiu YS, Wu YY et al (2009) Rapamycin protects against high fat diet-induced obesity in C57BL/6J mice. J Pharmacol Sci 109:496–503CrossRefPubMed
23.
Zurück zum Zitat Polak P, Hall MN (2009) mTOR and the control of whole body metabolism. Curr Opin Cell Biol 21:209–218CrossRefPubMed Polak P, Hall MN (2009) mTOR and the control of whole body metabolism. Curr Opin Cell Biol 21:209–218CrossRefPubMed
24.
Zurück zum Zitat Polak P, Cybulski N, Feige JN, Auwerx J, Ruegg MA, Hall MN (2008) Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab 8:399–410CrossRefPubMed Polak P, Cybulski N, Feige JN, Auwerx J, Ruegg MA, Hall MN (2008) Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab 8:399–410CrossRefPubMed
25.
Zurück zum Zitat Um SH, Frigerio F, Watanabe M et al (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200–205CrossRefPubMed Um SH, Frigerio F, Watanabe M et al (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200–205CrossRefPubMed
26.
Zurück zum Zitat Xiang X, Lan H, Tang H et al (2015) Tuberous sclerosis complex 1-mechanistic target of rapamycin complex 1 signaling determines brown-to-white adipocyte phenotypic switch. Diabetes 64:519–528CrossRefPubMed Xiang X, Lan H, Tang H et al (2015) Tuberous sclerosis complex 1-mechanistic target of rapamycin complex 1 signaling determines brown-to-white adipocyte phenotypic switch. Diabetes 64:519–528CrossRefPubMed
27.
Zurück zum Zitat Guertin DA, Stevens DM, Thoreen CC et al (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11:859–871CrossRefPubMed Guertin DA, Stevens DM, Thoreen CC et al (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11:859–871CrossRefPubMed
28.
Zurück zum Zitat Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA (2006) Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell 11:583–589CrossRefPubMed Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA (2006) Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell 11:583–589CrossRefPubMed
29.
Zurück zum Zitat Jones KT, Greer ER, Pearce D, Ashrafi K (2009) Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLoS Biol 7:e60PubMed Jones KT, Greer ER, Pearce D, Ashrafi K (2009) Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLoS Biol 7:e60PubMed
30.
Zurück zum Zitat Cybulski N, Polak P, Auwerx J, Ruegg MA, Hall MN (2009) mTOR complex 2 in adipose tissue negatively controls whole-body growth. Proc Natl Acad Sci U S A 106:9902–9907CrossRefPubMedPubMedCentral Cybulski N, Polak P, Auwerx J, Ruegg MA, Hall MN (2009) mTOR complex 2 in adipose tissue negatively controls whole-body growth. Proc Natl Acad Sci U S A 106:9902–9907CrossRefPubMedPubMedCentral
32.
Zurück zum Zitat Wang JQ, Liu RX, Wang F et al (2013) Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat Cell Biol 15:1455–1463CrossRefPubMed Wang JQ, Liu RX, Wang F et al (2013) Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat Cell Biol 15:1455–1463CrossRefPubMed
33.
Zurück zum Zitat Shan TZ, Liang XR, Bi PP, Kuang SH (2013) Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1 alpha-Fndc5 pathway in muscle. FASEB J 27:1981–1989CrossRefPubMedPubMedCentral Shan TZ, Liang XR, Bi PP, Kuang SH (2013) Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1 alpha-Fndc5 pathway in muscle. FASEB J 27:1981–1989CrossRefPubMedPubMedCentral
34.
Zurück zum Zitat Jeffery E, Berry R, Church CD et al (2014) Characterization of Cre recombinase models for the study of adipose tissue. Adipocytes 3:206–211CrossRef Jeffery E, Berry R, Church CD et al (2014) Characterization of Cre recombinase models for the study of adipose tissue. Adipocytes 3:206–211CrossRef
35.
Zurück zum Zitat Wang ZV, Deng Y, Wang QA, Sun K, Scherer PE (2010) Identification and characterization of a promoter cassette conferring adipocyte-specific gene expression. Endocrinology 151:2933–2939CrossRefPubMedPubMedCentral Wang ZV, Deng Y, Wang QA, Sun K, Scherer PE (2010) Identification and characterization of a promoter cassette conferring adipocyte-specific gene expression. Endocrinology 151:2933–2939CrossRefPubMedPubMedCentral
36.
Zurück zum Zitat Stanford KI, Middelbeek RJW, Townsend KL et al (2013) Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 123:215–223CrossRefPubMed Stanford KI, Middelbeek RJW, Townsend KL et al (2013) Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 123:215–223CrossRefPubMed
37.
Zurück zum Zitat Rosen ED, MacDougald OA (2006) Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 7:885–896CrossRefPubMed Rosen ED, MacDougald OA (2006) Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 7:885–896CrossRefPubMed
38.
Zurück zum Zitat Barquissau V, Beuzelin D, Giroud M et al (2014) PPAR gamma and PPAR alpha agonists induce white-to-brown conversion of human white adipocytes along with a metabolic shift from glucose to fatty acid oxidation. Diabetologia 57:S283 Barquissau V, Beuzelin D, Giroud M et al (2014) PPAR gamma and PPAR alpha agonists induce white-to-brown conversion of human white adipocytes along with a metabolic shift from glucose to fatty acid oxidation. Diabetologia 57:S283
39.
40.
Zurück zum Zitat Zhu MY, Chen D, Li DY et al (2013) Luteolin inhibits angiotensin II-induced human umbilical vein endothelial cell proliferation and migration through downregulation of Src and Akt phosphorylation. Circ J 77:772–779CrossRefPubMed Zhu MY, Chen D, Li DY et al (2013) Luteolin inhibits angiotensin II-induced human umbilical vein endothelial cell proliferation and migration through downregulation of Src and Akt phosphorylation. Circ J 77:772–779CrossRefPubMed
41.
Zurück zum Zitat Chang GR, Wu YY, Chiu YS et al (2009) Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice. Basic Clin Pharmacol 105:188–198CrossRef Chang GR, Wu YY, Chiu YS et al (2009) Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice. Basic Clin Pharmacol 105:188–198CrossRef
42.
43.
Zurück zum Zitat Dong F, Sun X, Liu W et al (2006) Pitx2 promotes development of splanchnic mesoderm-derived branchiomeric muscle. Development 133:4891–4899CrossRefPubMed Dong F, Sun X, Liu W et al (2006) Pitx2 promotes development of splanchnic mesoderm-derived branchiomeric muscle. Development 133:4891–4899CrossRefPubMed
44.
Zurück zum Zitat Shan TZ, Liu WY, Kuang SH (2013) Fatty acid binding protein 4 expression marks a population of adipocyte progenitors in white and brown adipose tissues. FASEB J 27:277–287CrossRefPubMedPubMedCentral Shan TZ, Liu WY, Kuang SH (2013) Fatty acid binding protein 4 expression marks a population of adipocyte progenitors in white and brown adipose tissues. FASEB J 27:277–287CrossRefPubMedPubMedCentral
45.
46.
47.
Zurück zum Zitat Monetti M, Levin MC, Watt MJ et al (2007) Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 6:69–78CrossRefPubMed Monetti M, Levin MC, Watt MJ et al (2007) Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 6:69–78CrossRefPubMed
48.
Zurück zum Zitat Chakrabarti P, English T, Shi J, Smas CM, Kandror KV (2010) Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage. Diabetes 59:775–781CrossRefPubMedPubMedCentral Chakrabarti P, English T, Shi J, Smas CM, Kandror KV (2010) Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage. Diabetes 59:775–781CrossRefPubMedPubMedCentral
49.
Zurück zum Zitat Kim JE, Chen J (2004) regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 53:2748–2756CrossRefPubMed Kim JE, Chen J (2004) regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 53:2748–2756CrossRefPubMed
50.
Zurück zum Zitat Martin SK, Fitter S, Dutta AK et al (2015) Brief report: the differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation. Stem Cells 33:1359–1365CrossRefPubMed Martin SK, Fitter S, Dutta AK et al (2015) Brief report: the differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation. Stem Cells 33:1359–1365CrossRefPubMed
Metadaten
Titel
Adipocyte-specific deletion of mTOR inhibits adipose tissue development and causes insulin resistance in mice
verfasst von
Tizhong Shan
Pengpeng Zhang
Qinyang Jiang
Yan Xiong
Yizhen Wang
Shihuan Kuang
Publikationsdatum
13.06.2016
Verlag
Springer Berlin Heidelberg
Erschienen in
Diabetologia / Ausgabe 9/2016
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-016-4006-4

Weitere Artikel der Ausgabe 9/2016

Diabetologia 9/2016 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.