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Evaluation of Glucose Uptake and Uncoupling Protein 1 Activity in Adipose Tissue of Diabetic Mice upon β-Adrenergic Stimulation

  • Narumi Kubo
  • Mio Kawahara
  • Yuko Okamatsu-Ogura
  • Yosuke Miyazaki
  • Ryuto Otsuka
  • Kazuki Fukuchi
Research Article
  • 127 Downloads

Abstract

Purpose

Regulation of metabolic activity in adipose tissue is of great concern for treating obesity. This study aimed to evaluate the adrenergic regulation of glucose uptake and the thermogenic program in adipose tissues in mouse models of both type 1 and 2 diabetes mellitus (DM).

Procedures

Male mice were treated with streptozotocin to induce type 1 (T1) DM, and obese ob/ob mice were used for the type 2 (T2) DM model. After selective β3-adrenoreceptor stimulation by CL 316,243 (CL) treatment, 2-deoxy-d-[14C]glucose ([14C]DG) was administered to DM and corresponding control mice. Radioactivity and uncoupling protein 1 (UCP1) expression were measured and analyzed in adipose tissues.

Results

In T1DM, [14C]DG uptake in brown adipose tissue (BAT) decreased both at rest and upon CL stimulation, and UCP1 expression was preserved. However, CL treatment enhanced [14C]DG uptake without impairing UCP1 expression in inguinal white adipose tissue (iWAT). In this model, CL could not alter blood glucose levels. In T2DM mice, the blood glucose level was significantly lowered by CL treatment. There was no decrease in CL-induced [14C]DG uptake in BAT, and UCP1 expression was maintained. However, [14C]DG uptake was not increased in iWAT and no UCP1 expression was observed in iWAT (browning).

Conclusions

The metabolic response against adrenergic stimulation varied depending on the type of adipose tissue and DM. This could be important for the therapeutic activation of adipose tissue metabolism in obese diabetic patients.

Key words

Adipose tissue Diabetes mellitus Glucose Uncoupling protein 

Notes

Acknowledgements

The authors thank Dr. Teruo Kawada (Graduate School of Agriculture, Kyoto University) for the kind gift of the anti-UCP1 antibody.

Compliance with Ethical Standards

Conflict of Interest

The authors have indicated that they have no financial conflict of interest.

References

  1. 1.
    Lo KA, Sun L (2013) Turning WAT into BAT: a review on regulators controlling the browning of white adipocytes. Biosci Rep 33:711–719CrossRefGoogle Scholar
  2. 2.
    Inokuma K, Ogura-Okamatsu Y, Toda C, Kimura K, Yamashita H, Saito M (2005) Uncoupling protein 1 is necessary for norepinephrine-induced glucose utilization in brown adipose tissue. Diabetes 54:1385–1391CrossRefPubMedGoogle Scholar
  3. 3.
    Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359CrossRefPubMedGoogle Scholar
  4. 4.
    Mirbolooki MR, Constantinescu CC, Pan ML, Mukherjee J (2011) Quantitative assessment of brown adipose tissue metabolic activity and volume using 18F-FDG PET/CT and β3-adrenergic receptor activation. EJNMMI Res 1:30CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JMAFL, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJJ (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360:1500–1508CrossRefPubMedGoogle Scholar
  6. 6.
    Feldmann HM, Golozoubova V, Cannon B, Nedergaard J (2009) UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 9:203–209CrossRefPubMedGoogle Scholar
  7. 7.
    Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bartness TJ, Ryu V (2015) Neural control of white, beige and brown adipocytes. Int J Obes Suppl 5:S35–S39CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50:536–546Google Scholar
  10. 10.
    Drel VR, Mashtalir N, Ilnytska O, Shin J, Li F, Lyzogubov VV, Obrosova IG (2006) The leptin-deficient (ob/ob) mouse: a new animal model of peripheral neuropathy of type 2 diabetes and obesity. Diabetes 55:3335–3343CrossRefPubMedGoogle Scholar
  11. 11.
    Strauss LG, Clorius JH, Schlag P, Lehner B, Kimmig B, Engenhart R, Marin-Grez M, Helus F, Oberdorfer F, Schmidlin P (1989) Recurrence of colorectal tumors: PET evaluation. Radiology 170:329–332CrossRefPubMedGoogle Scholar
  12. 12.
    Zasadny KR, Wahl RL (1993) Standardized uptake values of normal tissues at PET with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose: variations with body weight and a method for correction. Radiology 189:847–850CrossRefPubMedGoogle Scholar
  13. 13.
    Kanda Y (2013) Investigation of the freely-available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 48:452–458CrossRefPubMedGoogle Scholar
  14. 14.
    Baranwal A, Mirbolooki MR, Mukherjee J (2015) Initial assessment of β3-adrenoceptor-activated brown adipose tissue in streptozotocin-induced type 1 diabetes rodent model using [18F]fluorodeoxyglucose positron emission tomography/computed tomography. Mol Imaging 14:22–33CrossRefPubMedGoogle Scholar
  15. 15.
    Mirbolooki MR, Upadhyay SK, Constantinescu CC, Pan ML, Mukherjee J (2014) Adrenergic pathway activation enhances brown adipose tissue metabolism: a [18F]FDG PET/CT study in mice. Nucl Med Biol 41:10–16CrossRefPubMedGoogle Scholar
  16. 16.
    Buzelle SL, MacPherson RE, Peppler WT et al (2015) The contribution of IL-6 to beta 3 adrenergic receptor mediated adipose tissue remodeling. Physiol Rep 3:e12312CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Mössenböck K, Vegiopoulos A, Rose AJ, Sijmonsma TP, Herzig S, Schafmeier T (2014) Browning of white adipose tissue uncouples glucose uptake from insulin signaling. PLoS One 9:e110428CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wu C, Cheng W, Sun Y, Dang Y, Gong F, Zhu H, Li N, Li F, Zhu Z (2014) Activating brown adipose tissue for weight loss and lowering of blood glucose levels: a micro PET study using obese and diabetic model mice. PLoS One 9:e113742CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Nonogaki K (2000) New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia 43:533–549CrossRefPubMedGoogle Scholar
  20. 20.
    Fu L, Isobe K, Zeng Q, Suzukawa K, Takekoshi K, Kawakami Y (2008) The effects of beta(3)-adrenoceptor agonist CL-316,243 on adiponectin, adiponectin receptors and tumor necrosis factor-alpha expressions in adipose tissues of obese diabetic KKAy mice. Eur J Pharmacol 584:202–206CrossRefPubMedGoogle Scholar
  21. 21.
    Kumar A, Shiloach J, Betenbaugh MJ, Gallagher EJ (2015) The beta-3 adrenergic agonist (CL-316,243) restores the expression of down-regulated fatty acid oxidation genes in type 2 diabetic mice. Nutr Metab (Lond) 12:8CrossRefGoogle Scholar
  22. 22.
    Yoshitomi H, Yamazaki K, Abe S, Tanaka I (1998) Differential regulation of mouse uncoupling proteins among brown adipose tissue, white adipose tissue, and skeletal muscle in chronic beta 3 adrenergic receptor agonist treatment. Biochem Biophys Res Commun 253:85–91CrossRefPubMedGoogle Scholar
  23. 23.
    Olsen JM, Csikasz RI, Dehvari N et al (2017) β3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: mediation through the mTOR pathway. Mol Metab 30:611–619CrossRefGoogle Scholar
  24. 24.
    Hankir MK, Kranz M, Keipert S, Weiner J, Andreasen SG, Kern M, Patt M, Klöting N, Heiker JT, Brust P, Hesse S, Jastroch M, Fenske WK (2017) Dissociation between brown adipose tissue 18F-FDG uptake and thermogenesis in uncoupling protein 1-deficient mice. J Nucl Med 58:1100–1103CrossRefPubMedGoogle Scholar
  25. 25.
    Schade KN, Baranwal A, Liang C, Mirbolooki MR, Mukherjee J (2015) Preliminary evaluation of β3-adrenoceptor agonist-induced 18F-FDG metabolic activity of brown adipose tissue in obese Zucker rat. Nucl Med Biol 42:691–694CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mercer SW, Trayhurn P (1984) The development of insulin resistance in brown adipose tissue may impair the acute cold-induced activation of thermogenesis in genetically obese (ob/ob) mice. Biosci Rep 4:933–940CrossRefPubMedGoogle Scholar
  27. 27.
    Ishino S, Sugita T, Kondo Y, Okai M, Tsuchimori K, Watanabe M, Mori I, Hosoya M, Horiguchi T, Kamiguchi H (2017) Glucose uptake of the muscle and adipose tissues in diabetes and obesity disease models: evaluation of insulin and β3-adrenergic receptor agonist effects by 18F-FDG. Ann Nucl Med 31:413–423CrossRefPubMedGoogle Scholar
  28. 28.
    Gunawardana SC, Piston DW (2012) Reversal of type 1 diabetes in mice by brown adipose tissue transplant. Diabetes 61:674–682CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Abdullahi A, Jeschke MG (2016) White adipose tissue browning: a double edge sword. Trends Endocrinol Metab 27:542–552CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Hany TF, Gharehpapagh E, Kamel EM, Buck A, Himms-Hagen J, von Schulthess GK (2002) Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur J Nucl Med Mol Imaging 29:1393–1398CrossRefPubMedGoogle Scholar
  31. 31.
    Fukuchi K, Ono Y, Nakahata Y, Okada Y, Hayashida K, Ishida Y (2003) Visualization of interscapular brown adipose tissue using 99mTc-tetrofosmin in pediatric patients. J Nucl Med 44:1582–1585PubMedGoogle Scholar
  32. 32.
    Okuyama C, Sakane N, Yoshida T, Shima K, Kurosawa H, Kumamoto K, Ushijima Y, Nishimura T (2002) 123I- or 125I-metaiodobenzylguanidine visualization of brown adipose tissue. J Nucl Med 43:1234–1240PubMedGoogle Scholar
  33. 33.
    Mattsson CL, Csikasz RI, Chernogubova E, Yamamoto DL, Hogberg HT, Amri EZ, Hutchinson DS, Bengtsson T (2011) β1-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β3-adrenergic receptor-knockout mice via nonshivering thermogenesis. Am J Physiol Endocrinol Metab 301:E1108–E1118CrossRefPubMedGoogle Scholar
  34. 34.
    Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360:1509–1517CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Vijgen GH, Bouvy ND, Teule GJ et al (2012) Increase in brown adipose tissue activity after weight loss in morbidly obese subjects. J Clin Endocrinol Metab 97:E1229–E1233CrossRefPubMedGoogle Scholar
  36. 36.
    Kapke J, Shaheen Z, Kilari D, Knudson P, Wong S (2017) Immune checkpoint inhibitor-associated type 1 diabetes mellitus: case series, review of the literature, and optimal management. Case Rep Oncol 10:897–909CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© World Molecular Imaging Society 2018

Authors and Affiliations

  • Narumi Kubo
    • 1
  • Mio Kawahara
    • 1
  • Yuko Okamatsu-Ogura
    • 2
  • Yosuke Miyazaki
    • 1
  • Ryuto Otsuka
    • 1
  • Kazuki Fukuchi
    • 1
  1. 1.Department of Medical Physics and Engineering, Course of Health ScienceOsaka University Graduate School of MedicineOsakaJapan
  2. 2.Department of Biomedical Sciences, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan

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