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Erschienen in: Acta Diabetologica 2/2015

01.04.2015 | Original Article

Expression of S6K1 in human visceral adipose tissue is upregulated in obesity and related to insulin resistance and inflammation

verfasst von: Victoria Catalán, Javier Gómez-Ambrosi, Amaia Rodríguez, Beatriz Ramírez, Patricia Andrada, Fernando Rotellar, Víctor Valentí, Rafael Moncada, Pablo Martí, Camilo Silva, Javier Salvador, Gema Frühbeck

Erschienen in: Acta Diabetologica | Ausgabe 2/2015

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Abstract

The ribosomal protein S6 kinase 1 (S6K1) is a component of the insulin signalling pathway that has been proposed as a key molecular factor in insulin resistance development under conditions of nutrient overload. The aim was to evaluate the involvement of S6K1 in obesity as well as to explore their association with visceral adipose tissue (VAT) inflammation. Samples obtained from 40 subjects were used. Gene expression levels of RPS6KB1 and key inflammatory markers were analysed in VAT. The effect of insulin on transcript levels of RPS6KB1 in human differentiated adipocytes was also explored. RPS6KB1 mRNA levels in VAT were increased (P < 0.05) in obese patients. Insulin treatment significantly enhanced (P < 0.01) gene expression levels of RPS6KB1 and a positive association (P < 0.05) of RPS6KB1 expression with different markers of insulin resistance was observed. Moreover, RPS6KB1 gene expression levels were positively correlated with VAT gene expression levels of the inflammatory markers CCL2, CD68, MMP2, MMP9, VEGFA and CHI3L1 as well as with mRNA levels of MTOR and MAPK8, representative players involved in signalling pathways related to S6K1. The increased levels of S6K1 in obesity and its positive association with insulin resistance and inflammation suggest a role for this protein in the changes that take place in VAT in obesity establishing a link between inflammation and a higher risk for the development of metabolic diseases.
Literatur
1.
Zurück zum Zitat Frühbeck G, Toplak H, Woodward E, Yumuk V, Maislos M, Oppert JM (2013) Obesity: the gateway to ill health—an EASO position statement on a rising public health, clinical and scientific challenge in Europe. Obes Facts 6:117–120CrossRefPubMed Frühbeck G, Toplak H, Woodward E, Yumuk V, Maislos M, Oppert JM (2013) Obesity: the gateway to ill health—an EASO position statement on a rising public health, clinical and scientific challenge in Europe. Obes Facts 6:117–120CrossRefPubMed
2.
Zurück zum Zitat Ogden CL, Carroll MD, Kit BK, Flegal KM (2014) Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA 311:806–814CrossRefPubMed Ogden CL, Carroll MD, Kit BK, Flegal KM (2014) Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA 311:806–814CrossRefPubMed
3.
Zurück zum Zitat Frühbeck G, Gómez-Ambrosi J (2003) Control of body weight: a physiologic and transgenic perspective. Diabetologia 46:143–172PubMed Frühbeck G, Gómez-Ambrosi J (2003) Control of body weight: a physiologic and transgenic perspective. Diabetologia 46:143–172PubMed
4.
Zurück zum Zitat Frühbeck G, Gómez-Ambrosi J, Muruzábal FJ, Burrell MA (2001) The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab 280:E827–E847PubMed Frühbeck G, Gómez-Ambrosi J, Muruzábal FJ, Burrell MA (2001) The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab 280:E827–E847PubMed
5.
Zurück zum Zitat Poulain-Godefroy O, Lecoeur C, Pattou F, Frühbeck G, Froguel P (2008) Inflammation is associated with a decrease of lipogenic factors in omental fat in women. Am J Physiol Regul Integr Comp Physiol 295:R1–R7CrossRefPubMed Poulain-Godefroy O, Lecoeur C, Pattou F, Frühbeck G, Froguel P (2008) Inflammation is associated with a decrease of lipogenic factors in omental fat in women. Am J Physiol Regul Integr Comp Physiol 295:R1–R7CrossRefPubMed
6.
Zurück zum Zitat Frühbeck G (2008) Overview of adipose tissue and its role in obesity and metabolic disorders. Methods Mol Biol 456:1–22CrossRefPubMed Frühbeck G (2008) Overview of adipose tissue and its role in obesity and metabolic disorders. Methods Mol Biol 456:1–22CrossRefPubMed
8.
Zurück zum Zitat Catalán V, Gómez-Ambrosi J, Rodríguez A, Frühbeck G (2013) Adipose tissue immunity and cancer. Frontiers 4:275 Catalán V, Gómez-Ambrosi J, Rodríguez A, Frühbeck G (2013) Adipose tissue immunity and cancer. Frontiers 4:275
9.
Zurück zum Zitat Johnson AM, Olefsky JM (2013) The origins and drivers of insulin resistance. Cell 152:673–684CrossRefPubMed Johnson AM, Olefsky JM (2013) The origins and drivers of insulin resistance. Cell 152:673–684CrossRefPubMed
11.
Zurück zum Zitat Nicholson JK, Holmes E, Kinross J et al (2012) Host-gut microbiota metabolic interactions. Science 336:1262–1267CrossRefPubMed Nicholson JK, Holmes E, Kinross J et al (2012) Host-gut microbiota metabolic interactions. Science 336:1262–1267CrossRefPubMed
13.
Zurück zum Zitat Patti ME, Kahn BB (2004) Nutrient sensor links obesity with diabetes risk. Nat Med 10:1049–1050CrossRefPubMed Patti ME, Kahn BB (2004) Nutrient sensor links obesity with diabetes risk. Nat Med 10:1049–1050CrossRefPubMed
14.
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
15.
Zurück zum Zitat Um SH, D’Alessio D, Thomas G (2006) Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 3:393–402CrossRefPubMed Um SH, D’Alessio D, Thomas G (2006) Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 3:393–402CrossRefPubMed
16.
18.
Zurück zum Zitat Howell JJ, Ricoult SJ, Ben-Sahra I, Manning BD (2013) A growing role for mTOR in promoting anabolic metabolism. Biochem Soc Trans 41:906–912CrossRefPubMed Howell JJ, Ricoult SJ, Ben-Sahra I, Manning BD (2013) A growing role for mTOR in promoting anabolic metabolism. Biochem Soc Trans 41:906–912CrossRefPubMed
19.
Zurück zum Zitat Tremblay F, Brule S, Hee Um S et al (2007) Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. Proc Natl Acad Sci USA 104:14056–14061CrossRefPubMedCentralPubMed Tremblay F, Brule S, Hee Um S et al (2007) Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. Proc Natl Acad Sci USA 104:14056–14061CrossRefPubMedCentralPubMed
20.
Zurück zum Zitat Pende M, Kozma SC, Jaquet M et al (2000) Hypoinsulinaemia, glucose intolerance and diminished β-cell size in S6K1-deficient mice. Nature 408:994–997CrossRefPubMed Pende M, Kozma SC, Jaquet M et al (2000) Hypoinsulinaemia, glucose intolerance and diminished β-cell size in S6K1-deficient mice. Nature 408:994–997CrossRefPubMed
21.
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 USA 92:11086–11090CrossRefPubMedCentralPubMed Yeh WC, Bierer BE, McKnight SL (1995) Rapamycin inhibits clonal expansion and adipogenic differentiation of 3T3-L1 cells. Proc Natl Acad Sci USA 92:11086–11090CrossRefPubMedCentralPubMed
22.
Zurück zum Zitat Yang Z, Ming XF (2012) mTOR signalling: the molecular interface connecting metabolic stress, aging and cardiovascular diseases. Obes Rev 2:58–68CrossRef Yang Z, Ming XF (2012) mTOR signalling: the molecular interface connecting metabolic stress, aging and cardiovascular diseases. Obes Rev 2:58–68CrossRef
23.
Zurück zum Zitat Lim HK, Choi YA, Park W et al (2003) Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin-p70 S6 kinase 1 pathway. J Biol Chem 278:45117–45127CrossRefPubMed Lim HK, Choi YA, Park W et al (2003) Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin-p70 S6 kinase 1 pathway. J Biol Chem 278:45117–45127CrossRefPubMed
24.
Zurück zum Zitat Zhang J, Gao Z, Ye J (2013) Phosphorylation and degradation of S6K1 (p70S6K1) in response to persistent JNK1 Activation. Biochim Biophys Acta 2013:1980–1988CrossRef Zhang J, Gao Z, Ye J (2013) Phosphorylation and degradation of S6K1 (p70S6K1) in response to persistent JNK1 Activation. Biochim Biophys Acta 2013:1980–1988CrossRef
25.
Zurück zum Zitat Di R, Wu X, Chang Z et al (2012) S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt. Biochem J 441:199–207CrossRefPubMed Di R, Wu X, Chang Z et al (2012) S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt. Biochem J 441:199–207CrossRefPubMed
26.
Zurück zum Zitat Gómez-Ambrosi J, Silva C, Galofré JC et al (2012) Body mass index classification misses subjects with increased cardiometabolic risk factors related to elevated adiposity. Int J Obes 36:286–294CrossRef Gómez-Ambrosi J, Silva C, Galofré JC et al (2012) Body mass index classification misses subjects with increased cardiometabolic risk factors related to elevated adiposity. Int J Obes 36:286–294CrossRef
27.
28.
Zurück zum Zitat Gómez-Ambrosi J, Salvador J, Rotellar F et al (2006) Increased serum amyloid A concentrations in morbid obesity decrease after gastric bypass. Obes Surg 16:262–269CrossRefPubMed Gómez-Ambrosi J, Salvador J, Rotellar F et al (2006) Increased serum amyloid A concentrations in morbid obesity decrease after gastric bypass. Obes Surg 16:262–269CrossRefPubMed
29.
Zurück zum Zitat Muruzábal FJ, Frühbeck G, Gómez-Ambrosi J, Archanco M, Burrell MA (2002) Immunocytochemical detection of leptin in non-mammalian vertebrate stomach. Gen Comp Endocrinol 128:149–152CrossRefPubMed Muruzábal FJ, Frühbeck G, Gómez-Ambrosi J, Archanco M, Burrell MA (2002) Immunocytochemical detection of leptin in non-mammalian vertebrate stomach. Gen Comp Endocrinol 128:149–152CrossRefPubMed
30.
Zurück zum Zitat Catalán V, Gómez-Ambrosi J, Rodríguez A et al (2013) Increased levels of chemerin and its receptor, chemokine-like receptor-1, in obesity are related to inflammation: tumor necrosis factor-α stimulates mRNA levels of chemerin in visceral adipocytes from obese patients. Surg Obes Relat Dis 9:306–314CrossRefPubMed Catalán V, Gómez-Ambrosi J, Rodríguez A et al (2013) Increased levels of chemerin and its receptor, chemokine-like receptor-1, in obesity are related to inflammation: tumor necrosis factor-α stimulates mRNA levels of chemerin in visceral adipocytes from obese patients. Surg Obes Relat Dis 9:306–314CrossRefPubMed
31.
Zurück zum Zitat Catalán V, Gómez-Ambrosi J, Rotellar F et al (2007) Validation of endogenous control genes in human adipose tissue: relevance to obesity and obesity-associated type 2 diabetes mellitus. Horm Metab Res 39:495–500CrossRefPubMed Catalán V, Gómez-Ambrosi J, Rotellar F et al (2007) Validation of endogenous control genes in human adipose tissue: relevance to obesity and obesity-associated type 2 diabetes mellitus. Horm Metab Res 39:495–500CrossRefPubMed
32.
Zurück zum Zitat Catalán V, Gómez-Ambrosi J, Ramírez B et al (2007) Proinflammatory cytokines in obesity: impact of type 2 diabetes mellitus and gastric bypass. Obes Surg 17:1464–1474CrossRefPubMed Catalán V, Gómez-Ambrosi J, Ramírez B et al (2007) Proinflammatory cytokines in obesity: impact of type 2 diabetes mellitus and gastric bypass. Obes Surg 17:1464–1474CrossRefPubMed
33.
Zurück zum Zitat Krebs M, Roden M (2004) Nutrient-induced insulin resistance in human skeletal muscle. Curr Med Chem 11:901–908CrossRefPubMed Krebs M, Roden M (2004) Nutrient-induced insulin resistance in human skeletal muscle. Curr Med Chem 11:901–908CrossRefPubMed
34.
Zurück zum Zitat Dann SG, Selvaraj A, Thomas G (2007) mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med 13:252–259CrossRefPubMed Dann SG, Selvaraj A, Thomas G (2007) mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med 13:252–259CrossRefPubMed
35.
Zurück zum Zitat Khamzina L, Veilleux A, Bergeron S, Marette A (2005) 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 146:1473–1481CrossRefPubMed Khamzina L, Veilleux A, Bergeron S, Marette A (2005) 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 146:1473–1481CrossRefPubMed
36.
Zurück zum Zitat Moreno-Navarrete JM, Ortega F, Sanchez-Garrido MA et al (2013) Phosphorylated S6K1 (Thr389) is a molecular adipose tissue marker of altered glucose tolerance. J Nutr Biochem 24:32–38CrossRefPubMed Moreno-Navarrete JM, Ortega F, Sanchez-Garrido MA et al (2013) Phosphorylated S6K1 (Thr389) is a molecular adipose tissue marker of altered glucose tolerance. J Nutr Biochem 24:32–38CrossRefPubMed
37.
Zurück zum Zitat Krebs M, Brunmair B, Brehm A et al (2007) The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man. Diabetes 56:1600–1607CrossRefPubMed Krebs M, Brunmair B, Brehm A et al (2007) The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man. Diabetes 56:1600–1607CrossRefPubMed
38.
Zurück zum Zitat Tremblay F, Marette A (2001) Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem 276:38052–38060PubMed Tremblay F, Marette A (2001) Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem 276:38052–38060PubMed
39.
Zurück zum Zitat Adochio R, Leitner JW, Hedlund R, Draznin B (2009) Rescuing 3T3-L1 adipocytes from insulin resistance induced by stimulation of Akt-mammalian target of rapamycin/p70 S6 kinase (S6K1) pathway and serine phosphorylation of insulin receptor substrate-1: effect of reduced expression of p85α subunit of phosphatidylinositol 3-kinase and S6K1 kinase. Endocrinology 150:1165–1173CrossRefPubMed Adochio R, Leitner JW, Hedlund R, Draznin B (2009) Rescuing 3T3-L1 adipocytes from insulin resistance induced by stimulation of Akt-mammalian target of rapamycin/p70 S6 kinase (S6K1) pathway and serine phosphorylation of insulin receptor substrate-1: effect of reduced expression of p85α subunit of phosphatidylinositol 3-kinase and S6K1 kinase. Endocrinology 150:1165–1173CrossRefPubMed
40.
Zurück zum Zitat Zheng Y, Zhang W, Pendleton E et al (2009) Improved insulin sensitivity by calorie restriction is associated with reduction of ERK and p70S6 K activities in the liver of obese Zucker rats. J Endocrinol 203:337–347CrossRefPubMedCentralPubMed Zheng Y, Zhang W, Pendleton E et al (2009) Improved insulin sensitivity by calorie restriction is associated with reduction of ERK and p70S6 K activities in the liver of obese Zucker rats. J Endocrinol 203:337–347CrossRefPubMedCentralPubMed
41.
Zurück zum Zitat Treins C, Alliouachene S, Hassouna R, Xie Y, Birnbaum MJ, Pende M (2012) The combined deletion of S6K1 and Akt2 deteriorates glycemic control in a high-fat diet. Mol Cell Biol 32:4001–4011CrossRefPubMedCentralPubMed Treins C, Alliouachene S, Hassouna R, Xie Y, Birnbaum MJ, Pende M (2012) The combined deletion of S6K1 and Akt2 deteriorates glycemic control in a high-fat diet. Mol Cell Biol 32:4001–4011CrossRefPubMedCentralPubMed
42.
Zurück zum Zitat Lee DF, Kuo HP, Chen CT et al (2007) IKKβ suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130:440–455CrossRefPubMed Lee DF, Kuo HP, Chen CT et al (2007) IKKβ suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130:440–455CrossRefPubMed
43.
Zurück zum Zitat Zhang J, Gao Z, Yin J, Quon MJ, Ye J (2008) S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-α signaling through IKK2. J Biol Chem 283:35375–35382CrossRefPubMedCentralPubMed Zhang J, Gao Z, Yin J, Quon MJ, Ye J (2008) S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-α signaling through IKK2. J Biol Chem 283:35375–35382CrossRefPubMedCentralPubMed
44.
Zurück zum Zitat Humar R, Kiefer FN, Berns H, Resink TJ, Battegay EJ (2002) Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 16:771–780CrossRefPubMed Humar R, Kiefer FN, Berns H, Resink TJ, Battegay EJ (2002) Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 16:771–780CrossRefPubMed
45.
Zurück zum Zitat Wouters BG, Koritzinsky M (2008) Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer 8:851–864CrossRefPubMed Wouters BG, Koritzinsky M (2008) Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer 8:851–864CrossRefPubMed
46.
Zurück zum Zitat Yu Y, Sato JD (1999) MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor. J Cell Physiol 178:235–246CrossRefPubMed Yu Y, Sato JD (1999) MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor. J Cell Physiol 178:235–246CrossRefPubMed
47.
48.
Zurück zum Zitat Han MS, Jung DY, Morel C et al (2013) JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 339:218–222CrossRefPubMed Han MS, Jung DY, Morel C et al (2013) JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 339:218–222CrossRefPubMed
Metadaten
Titel
Expression of S6K1 in human visceral adipose tissue is upregulated in obesity and related to insulin resistance and inflammation
verfasst von
Victoria Catalán
Javier Gómez-Ambrosi
Amaia Rodríguez
Beatriz Ramírez
Patricia Andrada
Fernando Rotellar
Víctor Valentí
Rafael Moncada
Pablo Martí
Camilo Silva
Javier Salvador
Gema Frühbeck
Publikationsdatum
01.04.2015
Verlag
Springer Milan
Erschienen in
Acta Diabetologica / Ausgabe 2/2015
Print ISSN: 0940-5429
Elektronische ISSN: 1432-5233
DOI
https://doi.org/10.1007/s00592-014-0632-9

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