Skip to main content
Top
Published in: Molecular Imaging and Biology 2/2019

01-04-2019 | Research Article

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

Authors: Narumi Kubo, Mio Kawahara, Yuko Okamatsu-Ogura, Yosuke Miyazaki, Ryuto Otsuka, Kazuki Fukuchi

Published in: Molecular Imaging and Biology | Issue 2/2019

Login to get access

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.
Literature
1.
go back to reference Lo KA, Sun L (2013) Turning WAT into BAT: a review on regulators controlling the browning of white adipocytes. Biosci Rep 33:711–719CrossRef Lo KA, Sun L (2013) Turning WAT into BAT: a review on regulators controlling the browning of white adipocytes. Biosci Rep 33:711–719CrossRef
2.
go back to reference 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 54:1385–1391CrossRefPubMed 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 54:1385–1391CrossRefPubMed
3.
go back to reference 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
4.
go back to reference 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 1:30CrossRefPubMedPubMedCentral 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 1:30CrossRefPubMedPubMedCentral
5.
go back to reference 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 360:1500–1508CrossRefPubMed 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 360:1500–1508CrossRefPubMed
6.
go back to reference 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 9:203–209CrossRefPubMed 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 9:203–209CrossRefPubMed
7.
go back to reference 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 112:1821–1830CrossRefPubMedPubMedCentral 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 112:1821–1830CrossRefPubMedPubMedCentral
9.
go back to reference Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50:536–546 Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50:536–546
10.
go back to reference 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 55:3335–3343CrossRefPubMed 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 55:3335–3343CrossRefPubMed
11.
go back to reference 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 170:329–332CrossRefPubMed 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 170:329–332CrossRefPubMed
12.
go back to reference 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 189:847–850CrossRefPubMed 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 189:847–850CrossRefPubMed
13.
go back to reference Kanda Y (2013) Investigation of the freely-available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 48:452–458CrossRefPubMed Kanda Y (2013) Investigation of the freely-available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 48:452–458CrossRefPubMed
14.
go back to reference 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 14:22–33CrossRefPubMed 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 14:22–33CrossRefPubMed
15.
go back to reference 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 41:10–16CrossRefPubMed 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 41:10–16CrossRefPubMed
16.
go back to reference 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:e12312CrossRefPubMedPubMedCentral 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:e12312CrossRefPubMedPubMedCentral
17.
go back to reference 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:e110428CrossRefPubMedPubMedCentral 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:e110428CrossRefPubMedPubMedCentral
18.
go back to reference 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:e113742CrossRefPubMedPubMedCentral 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:e113742CrossRefPubMedPubMedCentral
19.
go back to reference Nonogaki K (2000) New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia 43:533–549CrossRefPubMed Nonogaki K (2000) New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia 43:533–549CrossRefPubMed
20.
go back to reference 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 584:202–206CrossRefPubMed 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 584:202–206CrossRefPubMed
21.
go back to reference 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) 12:8CrossRef 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) 12:8CrossRef
22.
go back to reference 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 253:85–91CrossRefPubMed 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 253:85–91CrossRefPubMed
23.
go back to reference 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 30:611–619CrossRef 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 30:611–619CrossRef
24.
go back to reference 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 58:1100–1103CrossRefPubMed 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 58:1100–1103CrossRefPubMed
25.
go back to reference 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 42:691–694CrossRefPubMedPubMedCentral 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 42:691–694CrossRefPubMedPubMedCentral
26.
go back to reference 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 4:933–940CrossRefPubMed 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 4:933–940CrossRefPubMed
27.
go back to reference 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 31:413–423CrossRefPubMed 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 31:413–423CrossRefPubMed
30.
go back to reference 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 29:1393–1398CrossRefPubMed 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 29:1393–1398CrossRefPubMed
31.
go back to reference 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 44:1582–1585PubMed 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 44:1582–1585PubMed
32.
go back to reference 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 43:1234–1240PubMed 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 43:1234–1240PubMed
33.
go back to reference 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–E1118CrossRefPubMed 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–E1118CrossRefPubMed
34.
go back to reference 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 360:1509–1517CrossRefPubMedPubMedCentral 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 360:1509–1517CrossRefPubMedPubMedCentral
35.
go back to reference 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–E1233CrossRefPubMed 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–E1233CrossRefPubMed
36.
go back to reference 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 10:897–909CrossRefPubMedPubMedCentral 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 10:897–909CrossRefPubMedPubMedCentral
Metadata
Title
Evaluation of Glucose Uptake and Uncoupling Protein 1 Activity in Adipose Tissue of Diabetic Mice upon β-Adrenergic Stimulation
Authors
Narumi Kubo
Mio Kawahara
Yuko Okamatsu-Ogura
Yosuke Miyazaki
Ryuto Otsuka
Kazuki Fukuchi
Publication date
01-04-2019
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology / Issue 2/2019
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-018-1251-6

Other articles of this Issue 2/2019

Molecular Imaging and Biology 2/2019 Go to the issue