Download PDF
Exp Clin Endocrinol Diabetes 2005; 113(8): 418-422
DOI: 10.1055/s-2005-865771
Article

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

The β3-Adrenergic Agonist CL316,243 Inhibits Insulin Signaling but not Glucose Uptake in Primary Human Adipocytes

M. M. Jost1 , P. Jost2 , J. Klein3 , H. H. Klein4
  • 1BioVisioN AG, Medical Research, Hannover, Germany
  • 2Department of Radiology, University of Bonn, Bonn, Germany
  • 3Department of Internal Medicine I, Medical University of Lübeck, Lübeck, Germany
  • 4Chairman of the Department of Internal Medicine 1, Berufsgenossenschaftliche Kliniken Bergmannsheil, Ruhr-University Bochum, Bochum, Germany
Further Information

Publication History

Received: June 10, 2004 First decision: October 14, 2004

Accepted: May 13, 2005

Publication Date:
08 September 2005 (online)

Also available at
    Permissions and Reprints

Abstract

Insulin resistance and obesity are central components of the metabolic syndrome which has become the leading cause of cardiovascular morbidity and mortality worldwide. Direct interactions of the β3-adrenoceptor system with adipocyte signaling and function in humans remain poorly understood. However, this might have important consequences for the regulation of energy homeostasis and insulin resistance in states of hyperinsulinemia and sympatho-adrenergic overactivity. We therefore investigated β3-adrenoceptor-mediated effects on insulin signaling and glucose uptake in mammary adipocytes of healthy women that underwent breast reduction surgery. Glucose uptake was strongly induced by insulin stimulation. This was paralleled by robust induction of insulin receptor kinase activity, insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity, and protein kinase B phosphorylation. Treatment with the β3-adrenoceptor-selective agonist CL316,243 alone, neither induced alterations in the early insulin signaling cascade nor changed the basal level of glucose uptake. By contrast, pretreatment with the β3-adrenoceptor agonist inhibited the insulin-induced insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity by 50 % and protein kinase B phosphorylation by 40 % without affecting insulin receptor kinase activity upstream. However, on the functional level insulin-induced glucose uptake remained unchanged by β3-adrenoceptor stimulation. Our data demonstrate an insulin receptor-independent negative influence of β3-adrenoceptor stimulation on proximal insulin signaling. This inhibition is apparently dissociated from glucose uptake in human adipocytes.

Key words

Insulin receptor - obesity - PD151746 - PI3 kinase - protein kinase B

References

  • 1 Alessi D R, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings B A. Mechanism of activation of protein kinase B by insulin and IGF-1.  EMBO Journal. 1996;  15 6541-6551
    PubMedGoogle Scholar
  • 2 Arch J R. beta(3)-Adrenoceptor agonists: potential, pitfalls and progress.  Eur J Pharmacol. 2002;  440 99-107
    CrossrefPubMedGoogle Scholar
  • 3 Arch J R, Ainsworth A T, Cawthorne M A, Piercy V, Sennitt M V, Thody V E, Wilson C, Wilson S. Atypical beta-adrenoceptor on brown adipocytes as target for anti- obesity drugs.  Nature. 1984;  309 163-165
    CrossrefPubMedGoogle Scholar
  • 4 Collins S, Cao W, Kiefer W, Dixon T, Medvedev A, Onuma H, Surwit R. Adrenoceptors, uncoupling proteins, and energy expenditure.  Experimental Biol Med. 2001;  226 982-990
    PubMedGoogle Scholar
  • 5 De Matteis R, Arch J, Petroni M, Ferrari D, Cinti S, Stock M. Immunohistochemical identification of the beta(3)-adrenoceptor in intact human adipocytes and ventricular myocardium: effect of obesity and treatment with ephedrine and caffeine.  Int J Obes Relat Metab Disord. 2002;  26 1442-1450
    CrossrefPubMedGoogle Scholar
  • 6 de Souza C, Burkey B. Beta 3-adrenoceptor agonists as anti-diabetic and anti-obesity drugs in humans.  Curr Pharm Des. 2001;  7 1433-1449
    CrossrefPubMedGoogle Scholar
  • 7 Ghorbani M, Himms-Hagen J. Appearance of brown adipocytes in white adipose tissue during CL 316,243-induced reversal of obesity and diabetes in Zucker fa/fa rats.  Int J Obes Relat Metab Disord. 1997;  21 465-475
    CrossrefPubMedGoogle Scholar
  • 8 Grujic D, Susulic V S, Harper M E, Himms-Hagen J, Cunningham B A, Corkey B E, Lowell B B. beta 3-adrenergic receptors on white and brown adipocytes mediate beta 3-selective agonis-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice.  J Biol Chem. 1997;  272 17686-17693
    CrossrefPubMedGoogle Scholar
  • 9 Hoffstedt J, Lönnqvist F, Shimizu M, Blaak E, Arner P. Effects of several putative β3-adrenoceptor agonists on lipolysis in human omental adipocytes.  Int J Obes. 1996;  20 428-434
    PubMedGoogle Scholar
  • 10 Hu B, Jennings L L. Orally bioavailable β3-adrenergic receptor agonists as potential therapeutic agents for obesity and type-II diabetes.  Prog Med Chem. 2003;  41 167-194
    PubMedGoogle Scholar
  • 11 Jost P, Fasshauer M, Kahn C, Benito M, Meyer M, Ott V, Lowell B, Klein H, Klein J. Atypical β-adrenergic effects on insulin signaling and action in β3-adrenoceptor-deficient brown adipocytes.  Am J Physiol Endocrinol Metab. 2002;  283 E146-E153
    PubMedGoogle Scholar
  • 12 Kitamura T, Ogawa W, Sakaue H. Requirement for activation of the serine-threonine kinase akt (Protein kinase B) in insulin stimulation of protein synthesis but not glucose transport.  Mol Cell Biol. 1998;  18 3708-3717
    PubMedGoogle Scholar
  • 13 Klein H H, Kowalewski B, Drenckhan M, Neugebauer S, Matthaei S, Kotzke G. A microtiter well assay system to measure insulin activation of insulin receptor kinase in intact human mononuclear cells.  Diabetes. 1993;  42 883-890
    PubMedGoogle Scholar
  • 14 Klein H H, Matthaei S, Drenkhan M, Ries W, Scriba P C. The relationship between insulin binding, insulin activation of insulin-receptor tyrosine kinase, and insulin stimulation of glucose uptake in isolated rat adipocytes. Effects of isoprenaline.  Biochem J. 1991;  274 787-792
    PubMedGoogle Scholar
  • 15 Klein H H, Vestergaard H, Kotzke G, Pedersen O. Elevation of serum insulin concentration during euglycemic hyperinsulinemic clamp studies leads to similar activation of insulin receptor kinase in skeletal muscle of subjects with and without NIDDM.  Diabetes. 1995;  44 1310-1317
    PubMedGoogle Scholar
  • 16 Klein J, Fasshauer M, Benito M, Kahn C R. Insulin and the beta3-adrenoceptor differentially regulate uncoupling protein-1 expression.  Mol Endocrinol. 2000;  14 764-773
    CrossrefPubMedGoogle Scholar
  • 17 Klein J, Fasshauer M, Ito M, Lowell B B, Benito M, Kahn C R. beta 3-adrenergic stimulation differentially inhibits insulin signaling and decreases insulin-induced glucose uptake in brown adipocytes.  J Biol Chem. 1999;  274 34795-34802
    CrossrefPubMedGoogle Scholar
  • 18 Krief S, Lonnqvist F, Raimbault S, Baude B, Van Spronsen A, Arner P, Strosberg A D, Ricquier D, Emorine L J. Tissue distribution of beta 3-adrenergic receptor mRNA in man.  J Clin Invest. 1993;  91 344-349
    PubMedGoogle Scholar
  • 19 Lawlor M A, Alessi D R. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses?.  J Cell Sci. 2001;  114 2903-2910
    PubMedGoogle Scholar
  • 20 Linder K, Arner P, Flores-Morales A, Tollet-Egnell P, Norstedt G. Differentially expressed genes in visceral or subcutaneous adipose tissue of obese men and women.  J Lipid Res. 2004;  45 148-154 Epub 2003 Oct, 2016
    PubMedGoogle Scholar
  • 21 Liu Y F, Herschkovitz A, Boura-Halfon S, Ronen D, Paz K, Leroith D, Zick Y. Serine phosphorylation proximal to its phosphotyrosine binding domain inhibits insulin receptor substrate 1 function and promotes insulin resistance.  Mol Cell Biol. 2004;  24 9668-9681
    CrossrefPubMedGoogle Scholar
  • 22 Lowell B, Flier J. Brown adipose tissue, b3-adrenergic receptors, and obesity.  Annu Rev Med. 1997;  48 307-316
    CrossrefPubMedGoogle Scholar
  • 23 Meyer M, Levin K, Grimmsmann T, Perwitz N, Eirich A, Beck-Nielsen H, Klein H H. Troglitazone treatment increases protein kinase B phosphorylation in skeletal muscle of normoglycemic subjects at risk for the development of type 2 diabetes.  Diabetes. 2002;  51 2691-2697
    PubMedGoogle Scholar
  • 24 Moeschel K, Beck A, Weigert C, Lammers R, Kalbacher H, Voelter W, Schleicher E D, Haring H U, Lehmann R. Protein kinase C-zeta-induced phosphorylation of Ser318 in insulin receptor substrate-1 (IRS-1) attenuates the interaction with the insulin receptor and the tyrosine phosphorylation of IRS-1.  J Biol Chem. 2004;  279 25157-25163
    CrossrefPubMedGoogle Scholar
  • 25 Nicholls D, Locke R. Thermogenic mechanisms in brown fat.  Physiol Rev. 1984;  64 1-64
    CrossrefPubMedGoogle Scholar
  • 26 Rondinone C M, Carvalho E, Wesslau C, Smith U P. Impaired glucose transport and protein kinase B activation by insulin, but not okadaic acid, in adipocytes from subjects with Type II diabetes mellitus.  Diabetologia. 1999;  42 819-825
    CrossrefPubMedGoogle Scholar
  • 27 Rondinone C M, Wang L M, Lonnroth P, Wesslau C, Pierce J H, Smith U. Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus.  Proc Natl Acad Sci U S A. 1997;  94 4171-4175
    CrossrefPubMedGoogle Scholar
  • 28 Smith U. Importance of the regional distribution of the adipose tissue-concluding remarks.  Acta Med Scand Suppl. 1988;  723 233-236
    PubMedGoogle Scholar
  • 29 Strosberg A. Towards the development and use of human-selective agonists for the pharmacologic treatment of obesity and diabetes.  J Endocrinol. 1997;  155
    PubMedGoogle Scholar
  • 30 Wang K KW, Nath R, Posner A, Raser K J, Buroker-Kilgore M, Hajimohammadreza I, Probert Jr A W, Marcoux F W, Ye Q, Takano E, Hatanaka M, Maki M, Caner H, Collins J L, Fergus A S, Lee K, Lunney E A, Hays S J, Yuen P W. An alpha-mercaptoacrylic acid derivative is a selective nonpeptide cell-permeable calpain inhibitor and is neuroprotective.  Proc Natl Acad Sci USA. 1996;  93 6687-6692
    CrossrefPubMedGoogle Scholar
  • 31 Weyer C, Tataranni P, Snitker S, Danforth E, Ravussin E. Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective beta3-adrenoceptor agonist in humans.  Diabetes. 1998;  47 1555-1561
    PubMedGoogle Scholar
  • 32 Whiteman E L, Cho H, Birnbaum M J. Role of Akt/protein kinase B in metabolism.  Trends Endocrinol Metab. 2002;  13 444-451
    CrossrefPubMedGoogle Scholar
  • 33 Wu X, Hoffstedt J, Deeb W, Singh R, Sedkova N, Zilbering A, Zhu L, Park P K, Arner P, Goldstein B J. Depot-specific variation in protein-tyrosine phosphatase activities in human omental and subcutaneous adipose tissue: a potential contribution to differential insulin sensitivity.  J Clin Endocrinol Metab. 2001;  86 5973-5980
    CrossrefPubMedGoogle Scholar
  • 34 Yanovski S Z, Yanovski J A. Obesity.  N Engl J Med. 2002;  346 591-602
    CrossrefPubMedGoogle Scholar

Ph.D. Marco M. Jost

Medical Research
BioVisioN AG

Feodor-Lynen-Str. 5

30625 Hannover

Germany

Phone: + 4951153889672

Fax: + 49 5 11 53 88 96 66

Email: m.jost@biovision-discovery.de