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Caloric restriction-associated remodeling of rat white adipose tissue: effects on the growth hormone/insulin-like growth factor-1 axis, sterol regulatory element binding protein-1, and macrophage infiltration

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Abstract

The role of the growth hormone (GH)-insulin-like growth factor (IGF)-1 axis in the lifelong caloric restriction (CR)-associated remodeling of white adipose tissue (WAT), adipocyte size, and gene expression profiles was explored in this study. We analyzed the WAT morphology of 6–7-month-old wild-type Wistar rats fed ad libitum (WdAL) or subjected to CR (WdCR), and of heterozygous transgenic dwarf rats bearing an anti-sense GH transgene fed ad libitum (TgAL) or subjected to CR (TgCR). Although less effective in TgAL, the adipocyte size was significantly reduced in WdCR compared with WdAL. This CR effect was blunted in Tg rats. We also used high-density oligonucleotide microarrays to examine the gene expression profile of WAT of WdAL, WdCR, and TgAL rats. The gene expression profile of WdCR, but not TgAL, differed greatly from that of WdAL. The gene clusters with the largest changes induced by CR but not by Tg were genes involved in lipid biosynthesis and inflammation, particularly sterol regulatory element binding proteins (SREBPs)-regulated and macrophage-related genes, respectively. Real-time reverse-transcription polymerase chain reaction analysis confirmed that the expression of SREBP-1 and its downstream targets was upregulated, whereas the macrophage-related genes were downregulated in WdCR, but not in TgAL. In addition, CR affected the gene expression profile of Tg rats similarly to wild-type rats. Our findings suggest that CR-associated remodeling of WAT, which involves SREBP-1-mediated transcriptional activation and suppression of macrophage infiltration, is regulated in a GH–IGF-1-independent manner.

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References

  • Al-Regaiey KA, Masternak MM, Bonkowski M, Sun L, Bartke A (2005) Long-lived growth hormone receptor knockout mice: interaction of reduced insulin-like growth factor I/insulin signaling and caloric restriction. Endocrinology 146:851–860

    Article  PubMed  CAS  Google Scholar 

  • Anderson R, Prolla T (2009) PGC-1alpha in aging and anti-aging interventions. Biochem Biophys Acta 1790:1059–1066

    Google Scholar 

  • Argmann C, Dobrin R, Heikkinen S, Auburtin A, Pouilly L, Cock TA, Koutnikova H, Zhu J, Schadt EE, Auwerx J (2009) Ppargamma2 is a key driver of longevity in the mouse. PLoS Genet 5:e1000752

    Article  PubMed  Google Scholar 

  • Bartke A (2005) Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146:3718–3723

    Article  PubMed  CAS  Google Scholar 

  • Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS (2001) Extending the lifespan of long-lived mice. Nature 414:412

    Article  PubMed  CAS  Google Scholar 

  • Barzilai N, Banerjee S, Hawkins M, Chen W, Rossetti L (1998) Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat. J Clin Invest 101:1353–1361

    Article  PubMed  CAS  Google Scholar 

  • Blüher M, Michael MD, Peroni OD, Ueki K, Carter N, Kahn BB, Kahn CR (2002) Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell 3:25–38

    Article  PubMed  Google Scholar 

  • Blüher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299:572–574

    Article  PubMed  Google Scholar 

  • Bonkowski MS, Rocha JS, Masternak MM, Al Regaiey KA, Bartke A (2006) Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc Natl Acad Sci U S A 103:7901–7905

    Article  PubMed  CAS  Google Scholar 

  • Brown-Borg HM, Borg KE, Mellska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384:33

    Article  PubMed  CAS  Google Scholar 

  • Chiu CH, Lin WD, Huang SY, Lee YH (2004) Effect of a C/EBP gene replacement on mitochondrial biogenesis in fat cells. Genes Dev 18:1970–1975

    Article  PubMed  CAS  Google Scholar 

  • Chung HY, Lee EK, Choi YJ, Kim JM, Kim DH, Zou Y, Kim CH, Lee J, Kim HS, Kim ND, Jung JH, Yu BP (2011) Molecular inflammation as an underlying mechanism of the aging process and age-related diseases. J Dent Res 90:830–840

    Article  PubMed  CAS  Google Scholar 

  • Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ (2000) Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141:2608–2613

    Article  PubMed  CAS  Google Scholar 

  • Farmer SR (2006) Transcriptional control of adipocyte formation. Cell Metab 4:263–273

    Article  PubMed  CAS  Google Scholar 

  • Flurkey K, Papaconstantinou J, Miller RA, Harrison DE (2001) Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A 98:6736–6741

    Article  PubMed  CAS  Google Scholar 

  • Frayn KN (2002) Adipose tissue as a buffer for daily lipid flux. Diabetologia 45:1201–1210

    Article  PubMed  CAS  Google Scholar 

  • Gesing A, Masternak MM, Wang F, Joseph AM, Leeuwenburgh C, Westbrook R, Lewinski A, Karbownik-Lewinska M, Bartke A (2011) Expression of key regulators of mitochondrial biogenesis in growth hormone receptor knockout (GHRKO) mice is enhanced but is not further improved by other potential life-extending interventions. J Gerontol A Biol Sci Med Sci 66:1062–1076

    Article  PubMed  Google Scholar 

  • Guarente L (2008) Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell 132:171–176

    Article  PubMed  CAS  Google Scholar 

  • Hancock CR, Han DH, Higashida K, Kim SH, Holloszy JO (2011) Does calorie restriction induce mitochondrial biogenesis? A reevaluation. FASEB J 25:785–791

    Article  PubMed  CAS  Google Scholar 

  • Higami Y, Pugh TD, Page GP, Allison DB, Prolla TA, Weindruch R (2004) Adipose tissue energy metabolism: altered gene expression profile of mice subjected to long-term caloric restriction. FASEB J 18:415–417

    PubMed  CAS  Google Scholar 

  • Higami Y, Yamaza H, Shimokawa I (2005) Laboratory findings of caloric restriction in rodents and primates. Adv Clin Chem 39:211–237

    Article  PubMed  Google Scholar 

  • Higami Y, Barger JL, Page GP, Allison DB, Smith SR, Prolla TA, Weindruch R (2006a) Energy restriction lowers the expression of genes linked to inflammation, the cytoskeleton, the extracellular matrix, and angiogenesis in mouse adipose tissue. J Nutr 136:343–352

    PubMed  CAS  Google Scholar 

  • Higami Y, Tsuchiya T, Chiba T, Yamaza H, Muraoka I, Hirose M, Komatsu T, Shimokawa I (2006b) Hepatic gene expression profile of lipid metabolism in rats: impact of caloric restriction and growth hormone/insulin-like growth factor-1 suppression. J Gerontol A Biol Sci Med Sci 61:1099–1110

    Article  PubMed  Google Scholar 

  • Holzenberger M, Dupont J, Ducos B, Leneuve P, Géloën A, Even PC, Cervera P, Le Bouc Y (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187

    Article  PubMed  CAS  Google Scholar 

  • Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, Goldstein JL (2003) Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci U S A 100:12027–12032

    Article  PubMed  CAS  Google Scholar 

  • Jackson JE (2005) A user’s guide to principal components. Wiley, New York

    Google Scholar 

  • Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116:1494–1505

    Article  PubMed  CAS  Google Scholar 

  • Kawanishi N, Yano H, Yokogawa Y, Suzuki K (2010) Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice. Exerc Immunol Rev 16:105–118

    PubMed  Google Scholar 

  • Konishi T, Konishi F, Takasaki S, Inoue K, Nakayama K, Konagaya A (2008) Coincidence between transcriptome analyses on different microarray platforms using a parametric framework. PLoS One 3:e3555

    Article  PubMed  Google Scholar 

  • Koo H-Y, Miyashita M, Cho BH, Nakamura MT (2009) Replacing dietary glucose with fructose increases ChREBP activity and SREBP-1 protein in rat liver nucleus. Biochem Biophys Res Commun 390:285–289

    Article  PubMed  CAS  Google Scholar 

  • López-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, Cascajo MV, Allard J, Ingram DK, Navas P, de Cabo R (2006) Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA 103:1768–1773

    Google Scholar 

  • Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184

    Article  PubMed  CAS  Google Scholar 

  • Masoro EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev 126:913–922

    Article  PubMed  CAS  Google Scholar 

  • Masternak MM, Bartke A, Wang F, Spong A, Gesing A, Fang Y, Salmon AB, Hughes LF, Liberati T, Boparai R, Kopchick JJ, Westbrook R (2012) Metabolic effects of intra-abdominal fat in GHRKO mice. Aging Cell 11:73–81

    Article  PubMed  CAS  Google Scholar 

  • Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E, Moncada S, Carruba MO (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310:314–317

    Article  PubMed  CAS  Google Scholar 

  • Okita N, Hayashida Y, Kojima Y, Fukushima M, Yuguchi K, Mikami K, Yamauchi A, Watanabe K, Noguchi M, Nakamura M, Toda T, Higami Y (2012) Differential responses of white adipose tissue and brown adipose tissue to caloric restriction in rats. Mech Ageing Dev 133:255–266

    Article  PubMed  CAS  Google Scholar 

  • Osborne TF (2000) Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action. J Biol Chem 275:32379–32382

    Article  PubMed  CAS  Google Scholar 

  • Osborne TF, Espenshade PJ (2009) Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it’s been. Genes Dev 23:2578–2591

    Article  PubMed  CAS  Google Scholar 

  • Otabe S, Yuan X, Fukutani T, Wada N, Hashinaga T, Nakayama H, Hirota N, Kojima M, Yamada K (2007) Overexpression of human adiponectin in transgenic mice results in suppression of fat accumulation and prevention of premature death by high-calorie diet. Am J Physiol Endocrinol Metab 293:E210–E218

    Article  PubMed  CAS  Google Scholar 

  • Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11:85–97

    Article  PubMed  CAS  Google Scholar 

  • Saely CH, Geiger K, Drexel H (2012) Brown versus white adipose tissue: a mini-review. Gerontology 58:15–23

    Article  PubMed  Google Scholar 

  • Shi T, Wang F, Stieren E, Tong Q (2005) SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J Biol Chem 280:13560–13567

    Google Scholar 

  • Shimokawa I, Higami Y, Utsuyama M, Tuchiya T, Komatsu T, Chiba T, Yamaza H (2002) Life span extension by reduction in growth hormone-insulin-like growth factor-1 axis in a transgenic rat model. Am J Pathol 160:2259–2265

    Article  PubMed  CAS  Google Scholar 

  • Shimokawa I, Higami Y, Tsuchiya T, Otani H, Komatsu T, Chiba T, Yamaza H (2003) Life span extension by reduction of the growth hormone-insulin-like growth factor-1 axis: relation to caloric restriction. FASEB J 17:1108–1109

    PubMed  CAS  Google Scholar 

  • Sinclair DA (2005) Toward a unified theory of caloric restriction and longevity regulation. Mech Ageing Dev 126:987–1002

    Article  PubMed  CAS  Google Scholar 

  • Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273:59–63

    Article  PubMed  CAS  Google Scholar 

  • Torres-Leal FL, Fonseca-Alaniz MH, Rogero MM, Tirapegui J (2010) The role of inflamed adipose tissue in the insulin resistance. Cell Biochem Funct 28:623–631

    Article  PubMed  CAS  Google Scholar 

  • Weindruch R, Walford RL (1988) The retardation of aging and disease by dietary restriction. Charles C Thomas, Springfield

    Google Scholar 

  • Yamaza H, Komatsu T, Chiba T, Toyama H, To K, Higami Y, Shimokawa I (2004) A transgenic dwarf rat model as a tool for the study of calorie restriction and aging. Exp Gerontol 39:269–272

    Article  PubMed  CAS  Google Scholar 

  • Yamaza H, Komatsu T, To K, Toyama H, Chiba T, Higami Y, Shimokawa I (2007) Involvement of insulin-like growth factor-1 in the effect of caloric restriction: regulation of plasma adiponectin and leptin. J Gerontol A Biol Sci Med Sci 62:27–33

    Article  PubMed  Google Scholar 

  • Yang J, Goldstein JL, Hammer RE, Moon YA, Brown MS, Horton JD (2001) Decreased lipid synthesis in livers of mice with disrupted site-1 protease gene. Proc Natl Acad Sci 98:13607–13612

    Article  PubMed  CAS  Google Scholar 

  • Yu BP (1994) Modulation of aging processes by dietary restriction. CRC, Boca Raton

    Google Scholar 

Download references

Acknowledgments

We thank Yutaka Araki and Yuko Moriyama (Department of Investigative Pathology, Nagasaki University Graduate School for Biomedical Sciences) for their technical assistance and cooperation. This work was supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (no. 19590396).

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Authors and Affiliations

  1. Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan

    Yoshikazu Chujo, Namiki Fujii, Naoyuki Okita, Takumi Narita, Atsushi Yamada, Yushi Haruyama & Yoshikazu Higami

  2. Molecular Genetics Group, Akita Prefectural University, Akita, Japan

    Tomokazu Konishi

  3. Graduate School of Bioresource and Bioenvironmental Sciences, Molecular Gene Technics, Kyushu University, Fukuoka, Japan

    Kosuke Tashiro

  4. Department of Investigative Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Takuya Chiba & Isao Shimokawa

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  1. Yoshikazu Chujo
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Correspondence to Yoshikazu Higami.

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Yoshikazu Chujo, Namiki Fujii, Naoyuki Okita, and Tomokazu Konishi contributed equally to this work.

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Chujo, Y., Fujii, N., Okita, N. et al. Caloric restriction-associated remodeling of rat white adipose tissue: effects on the growth hormone/insulin-like growth factor-1 axis, sterol regulatory element binding protein-1, and macrophage infiltration. AGE 35, 1143–1156 (2013). https://doi.org/10.1007/s11357-012-9439-1

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