¯3 Adrenoreceptor

The Beta-3 Adrenoreceptor plays an important role in regulating human fat storage and variants of this receptor are thought to be relevant to diabetes.In addition to the major interest in obesity and diabetes expressed by the pharmaceutical industry, increasing numbers of academic groups are attracted by this general research area. This renewed interest is of course in part stimulated by available financing from industry. It also reflects the growing realisation that metabolism remains an open frontier: little is known about adipocyte sub-populations, specific markers, or endocrine functions. Research on the ß3 adrenoreceptor and discussion about the hypothetical ß4 adrenoreceptor is currently stimulating considerable interest which will certainly be satisfied by this volume. The Beta-3 Adrenoreceptor will appeal to readers at graduate and post-graduate levels of all major universities and other research and education institutes.

A. Donny Strosberg is Vice-president of the Cochin Institute for Molecular Genetics, and Director of the CNRS Unit of Molecular Immunopharmacology in Paris.

List of figures

x

List of tables

xii

Contributors

xiii

Preface

xv

Abbreviations used in this book

xvii

Structure and Function of the β3-Adrenoreceptor

1

(19)

A. Donny Strosberg

Cindy C. Gerhardt

Introduction

1

(1)

The β3AR gene

2

(2)

Cloning of the gene

2

(1)

Structure of the coding region

3

(1)

Structure of the promoter

3

(1)

The β3AR protein

4

(6)

Comparison with β1- and β2AR

4

(3)

Comparison of β3AR from various species

7

(2)

Polymorphism

9

(1)

Structure-function relationships in the β3AR

10

(2)

The ligand binding site

10

(1)

The regions of interaction with the G proteins

11

(1)

Signal transduction and biological functions

12

(3)

β3AR-mediated activation of adenylyl cyclase

12

(2)

β3AR-mediated activation of other signalling pathways

14

(1)

A role for the β3AR in adipocyte differentiation

15

(1)

Distribution of the β3AR

15

(4)

Functional detection of the β3AR

16

(1)

Immunodetection of the β3AR protein

17

(1)

Detection of the β3AR mRNA

18

(1)

Concluding remarks

19

(1)

Acknowledgements

19

(1)

Regulation of the β3-Adrenoreceptor Signalling Efficacy

20

(16)

Michel Bouvier

Introduction

20

(2)

The β-adrenoreceptors and their signalling pathways

21

(1)

General concepts of G protein-coupled signalling regulation

22

(5)

Agonist-promoted receptor phosphorylation and receptor uncoupling

22

(2)

Receptor sequestration; a process involved in desensitization and resensitization

24

(2)

Agonist-promoted down-regulation

26

(1)

The β3-adrenoreceptor, a prototypic system to study subtype-specific regulation

27

(2)

Comparative analysis of the structural determinants of receptor regulation

27

(2)

The β3-adrenoreceptor is resistant to rapid agonist-promoted uncoupling and sequestration

29

(1)

Cell type-specific down-regulation of the β3-adrenoreceptor

30

(3)

Use of chimeric β3/β2-adrenoreceptors to delineate regulatory motifs

33

(1)

Potential physiological consequences of the relative resistance of the β3-adrenoreceptor to desensitization

34

(1)

Conclusions

35

(1)

Using Transgenic and Gene Knockout Techniques to Assess β3-Adrenoreceptor Function

36

(12)

Bradford B. Lowell

Vedrana S. Susulic

Danica Grujic

Moriko Ito

Introduction

36

(1)

Mice lacking β3AR

36

(4)

Phenotype of mice lacking β3AR

36

(2)

Effects of β3AR deficiency on catecholamine-mediated stimulation of adenylyl cyclase and lipolysis in adipocytes

38

(2)

Effects of β3AR deficiency on in vivo effects of CL-316,243

40

(1)

Role of β3AR on white versus brown adipocytes in mediating effects of β3-selective agonists on energy expenditure, insulin secretion and food intake

40

(3)

Role of white versus brown adipocyte β3AR in mediating effects of CL-316,243 on energy expenditure

41

(1)

Role of white versus brown adipocyte β3AR in mediating effects of CL-316,243 on insulin secretion

42

(1)

Role of white versus brown adipocyte β3AR in mediating effects of CL-316,243 on food intake

42

(1)

Creation of mice which express human, but not murine, β3AR

43

(3)

Using β3AR gene knockout mice to study `β4AR' activity

46

(1)

Evidence for the existence of `β4AR'

46

(1)

Assessment of `β4AR' activity in β3AR gene knockout mice

47

(1)

Conclusions

47

(1)

Acknowledgements

47

(1)

β3-Adrenoreceptor Ligands and the Pharmacology of the β3-Adrenoreceptor

48

(29)

Jonathan R.S. Arch

Introduction

48

(1)

Antagonists

49

(6)

β1/2AR-selective antagonists

49

(3)

Non-selective and β3AR-selective antagonists

52

(3)

Agonists

55

(19)

β1/2AR-selective agonists

55

(1)

Arylethanolamine β3AR-selective agonists

55

(11)

Aryloxypropanolamine β3AR agonists

66

(6)

Trimetoquinol and analogues

72

(1)

Metabolism and pharmacokinetics

73

(1)

Idiosyncrasies of β3AR pharmacology

74

(2)

Relative agonist potencies vary with the nature of the assay

74

(1)

Prediction of human tissue pharmacology from cloned receptor pharmacology

75

(1)

Conclusions

76

(1)

The Native Human β3-Adrenoreceptor

77

(10)

Peter Arner

Fredrik Lonnqvist

Introduction

77

(1)

The human β3AR gene

77

(1)

Tissue expression of mRNA for β3AR

78

(4)

White adipose tissue

78

(2)

Brown adipose tissue

80

(1)

Heart

81

(1)

Colon

81

(1)

Brain

81

(1)

Urinary bladder

81

(1)

Other tissues

82

(1)

Is there a fourth βAR?

82

(1)

Structural variations in the native human β3AR

83

(1)

β3AR as a therapeutic target

84

(1)

Conclusions

85

(2)

β3-Adrenoreceptor-Mediated Responses in Heart and Vessels

87

(10)

Max Lafontan

Dominique Langin

Jean Galitzky

Michel Berlan

Chantal Gauthier

Genevieve Tavernier

Introduction

87

(1)

βAR subtypes in the heart

87

(4)

Functional β3AR in the human heart

88

(2)

The putative β4AR in cardiac tissue

90

(1)

β3AR-mediated vasodilatation

91

(2)

β3AR regulation of blood flow

93

(2)

Regulation of pancreatic islet blood flow

93

(2)

Regulation of gastric mucosal blood flow

95

(1)

β3AR-mediated cardiovascular effects

95

(1)

Conclusions and future trends

95

(2)

β3-Adrenoreceptors in Brown and White Adipocytes: Roles in Thermogenesis and Energy Balance

97

(23)

Jean Himms-Hagen

Introduction

97

(1)

Brown and white adipocytes and tissues

98

(7)

Functions of brown and white adipocytes

98

(1)

Definition and tissue distribution of brown and white adipocytes

99

(2)

Definition of BAT and WAT

101

(1)

Multiple UCPs in BAT

101

(1)

Adrenoreceptors in brown adipocytes

102

(1)

Control of brown adipocytes by the sympathetic nervous system and the hypothalamus

103

(1)

Central and peripheral effects of insulin in maintenance of thermogenic capacity of BAT

104

(1)

Control of blood flow in BAT by the sympathetic nervous system and the hypothalamus

105

(1)

Origin of brown adipocytes

105

(7)

Differentiation of brown adipocytes and mitochondriogenesis

105

(3)

Induction of hyperplasia of brown adipocytes in BAT

108

(1)

Expression of multiple UCPs in brown adipocytes: function and regulation

109

(1)

Induction of emergence of `ectopic' brown adipocytes in WAT

109

(1)

Is there more than one type of brown adipocyte?

110

(2)

Physiological functions of brown adipose tissue

112

(3)

Role in thermoregulation in a cold environment

112

(1)

Role in food intake

113

(1)

Role in defence against obesity

113

(2)

Secretions from brown adipocytes

115

(2)

Satiety factors

115

(1)

Other factors

116

(1)

β3ARs in brown and white adipocytes as a target for anti-obesity and anti-diabetes drugs

117

(2)

Perspective

119

(1)

The Putative `β4'-Adrenoreceptor and Other Atypical β-Adrenoreceptors

120

(5)

A. Donny Strosberg

Jonathan R.S. Arch

Introduction

120

(1)

Pharmacology of the β4AR and other atypical βARs

120

(1)

A summary of `β4'AR pharmacology

121

(2)

The search for molecular evidence for atypical βARs

123

(2)

The discovery of the β3AR gene and other putative homologues

123

(1)

The discovery of a receptor which binds iodocyanopindolol and other β3AR ligands

123

(1)

Non-β3AR-like pharmacological properties of β3AR proteins

123

(2)

References

125

(42)

Index

167

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