Adrenergic receptor polymorphisms and autonomic nervous system function in human obesity

doi:10.1016/j.tem.2006.07.001

Trends in Endocrinology & Metabolism

Volume 17, Issue 7, September 2006, Pages 269-275

https://doi.org/10.1016/j.tem.2006.07.001 Get rights and content

Adrenergic receptors (ARs) are cell-surface G-protein-coupled receptors for catecholamines. They are essential components of the sympathetic nervous system, organized within the autonomic nervous system (ANS), which controls various physiological functions, including energy homeostasis and metabolism of glucose and lipids. An impairment of ANS function in metabolism is considered to be one of the pathological states associated with human obesity and related metabolic diseases; thus, alterations in AR function might be implicated in the pathophysiology of these diseases. Several studies have suggested an association between obesity phenotypes and some AR polymorphisms. In vitro and human clinical studies indicate that some of these polymorphisms have functional and pathophysiological significance, including the linkage to ANS function. This review summarizes present knowledge of AR polymorphisms related to human obesity, and their association with ANS function.

Introduction

The autonomic nervous system (ANS) is essential in maintaining organismic homeostasis, including the regulation of both the cardiovascular system and energy balance, and maintenance of sympathovagal balance, abnormalities of which are all assumed to be associated with the etiology and pathology of obesity and related complications such as hypertension, diabetes and cardiovascular disease 1, 2, 3. It is well known that the adrenergic system is important in the regulation of energy balance through thermogenesis and lipid mobilization, which are under the control of the ANS 1, 3.

Over the past few decades, much evidence as to the heritable characteristic of human obesity has come from studies on the polymorphisms in certain adrenergic receptor (AR) subtype genes (Table 1). The Trp64Arg mutation of the β₃-AR has been, to a great extent, investigated in association with obesity or related phenotypes. Furthermore, the combined effects of β₃-AR Trp64Arg and other polymorphisms [e.g. uncoupling protein 1 gene (UCP1) promoter polymorphism] on body weight gain were also demonstrated. Recently, α₂-AR subtype (especially α_2A- and α_2B-AR) polymorphisms have been investigated for their etiological role in obesity and related pathophysiological states.

These observations raise the possibility that genetic variation in adrenergic system might be associated with autonomic modulation, which might contribute to the pathology of human obesity. The purpose of this review is to provide an overview of the prevalent relationship between the AR genetic polymorphisms and obesity or related pathologies, with emphasis on their association with ANS function.

Section snippets

Autonomic nervous system function in human obesity

The ANS is a key contributor in the regulation of energy balance and lipid metabolism. Obese subjects have been reported to have increased plasma or urinary catecholamine levels and higher muscle sympathetic nervous activity 4, 5, which suggests that chronic increased sympathetic stimulation is one of the pathological features of human obesity. However, in regard to the etiology of obesity, not only altered presynaptic sympathetic nerve activity, but also blunted responsiveness to sympathetic

Association of α_2B-adrenergic receptor polymorphism with ANS function

The α₂-AR is involved in energy expenditure through both central and peripheral autonomic regulation. The association of α_2B-AR polymorphism with ANS function, as reflected by HRV, was recently investigated in young and healthy subjects [56]. In this study, the subjects with the Glu⁹/Glu⁹ genotypes had significantly greater LF and VLF spectral powers of HRV than did wild-type α_2B-AR (Glu¹²/Glu¹²) carriers at supine rest. Moreover, higher sympathetic activity and lower parasympathetic activity,

Polymorphisms in other adrenergic receptors and AR-related components (G proteins) and in relation to human obesity

Because both β₁- and β₂-ARs, as well as the β₃-AR, mediate lipolysis and energy expenditure in response to sympathetic stimulation in adipose tissue and muscle, both receptor genes can be regarded as candidate genes for human obesity. However, few reports on the association between the two β₁-AR polymorphisms (Ser49Gly and Arg389Gly) [22] and obesity phenotypes have been published to date 58, 59 (Table 1). These studies demonstrated that the Gly49 genotype was important for long-term changes in

Summary

Attenuation of autonomic activity contributes to the etiology and development of obesity. Thus, genetic polymorphisms that affect autonomic function, such as AR polymorphisms, are reasonable causes for human obesity. Many studies have investigated the association of AR polymorphisms with obesity and related clinical features, including reduced BMR, lowered lipolytic activity and blunted autonomic response in middle-aged or older patients with obesity. Some recent studies using HRV analysis have

Acknowledgements

This study was supported by a grant provided by the Ministry of Education, Culture, Sports, Science and Technology, Japan, as part of the 21st Century COE program ‘Knowledge Information Infrastructure for Genome Science’.

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Citation Excerpt :
During the test, the respiratory rate was controlled at 0.25 Hz (15 breaths per minute) by means of an electric metronome, to reduce significant variations in HRV spectral powers resulting from individual variations in breathing frequency and to avoid interference with the LF component by the parasympathetic component.23 The R-R interval power spectral analysis procedures have been described previously.13,14 Briefly, the ECG R-R interval data obtained from the CM5 lead were digitized at 1000 Hz, and the derived R-R interval time series were then aligned in a 2-Hz sequence for power spectral analysis.
The β₁- and β₂-adrenergic receptors (ARs) coexist in the human heart and control sympathetic responses. Several functional genetic variations in the β-AR genes (ADRB1 or ADRB2) have been identified and implicated as causes of hypertension and cardiovascular disease. We assessed the relationship between 4 representative genetic polymorphisms of β-AR (Ser49Gly and Arg389Gly in β₁-AR, Arg16Gly and Gln27Glu in β₂-AR) and autonomic nervous system (ANS) function in healthy young Japanese males.
One hundred forty-nine subjects were genotyped for each β-AR polymorphism and underwent evaluation of ANS function by power spectral analysis of heart rate variability (HRV) during supine rest and in a standing position. The low-frequency (LF; <0.15 Hz) and high-frequency (HF; >0.15 Hz) components of HRV were quantified by frequency domain analysis and expressed in absolute and normalized units.
The β₂-AR Arg16 homozygous group had a significantly lower diastolic and mean blood pressure than the Gly16 group in both Arg16Gly individual and Gln27Glu polymorphism combined diplotype-based analyses. In a supine rest position, subjects homozygous for the β₂-AR Arg16 allele had significantly lower HRV sympathetic indices (LF [%] and LF/HF ratio) but higher HRV parasympathetic indices (HF [%]) than the Gly16 allele carriers. Meanwhile, the β₂-AR Glu27 allele was significantly associated with higher HRV LF power than were Gln27 homozygous subjects. In the analysis of gene-gene interaction, the effects of the β₂-AR Arg16 homozygotes on HRV were more apparent in the presence of the β₁-AR Gly389allele. No independent associations were observed between the β₁-AR Ser49Gly or Arg389Gly genotypes and HRV indices.
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Trends in Endocrinology & Metabolism

ReviewAdrenergic receptor polymorphisms and autonomic nervous system function in human obesity

Introduction

Section snippets

Autonomic nervous system function in human obesity

Association of α2B-adrenergic receptor polymorphism with ANS function

Polymorphisms in other adrenergic receptors and AR-related components (G proteins) and in relation to human obesity

Summary

Acknowledgements

FEBS Lett.

Int. J. Cardiol.

Am. J. Cardiol.

J. Biol. Chem.

Lancet

J. Lipid Res.

J. Biol. Chem.

Int. J. Cardiol.

Metabolism

J. Biol. Chem.

Trends Pharmacol. Sci.

Am. J. Hypertens.

Fat cells: afferent and efferent messages define new approaches to treat obesity

Annu. Rev. Pharmacol. Toxicol.

The sympathetic nervous system and obesity: role in aetiology and treatment

Obes. Rev.

The peripheral sympathetic nervous system in human obesity

Obes. Rev.

Sympathetic nervous system activity, body fatness, and body fat distribution in younger and older males

J. Appl. Physiol.

Body fat and sympathetic nerve activity in healthy subjects

Circulation

Chronic sympathetic activation: consequence and cause of age-associated obesity?

Diabetes

betaAR signaling required for diet-induced thermogenesis and obesity resistance

Science

Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology

Circulation

Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control

Science

Power spectral analysis of heart rate variability in obese subjects: evidence of decreased cardiac sympathetic responsiveness

Int. J. Obes. Relat. Metab. Disord.

Autonomic cardiovascular regulation in obesity

J. Endocrinol.

Autonomic responsiveness to acute cold exposure in obese and non-obese young women

Int. J. Obes. Relat. Metab. Disord.

Physiological consequences of beta-adrenergic receptor disruption

J. Mol. Med.

Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity

N. Engl. J. Med.

Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene

N. Engl. J. Med.

Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns

N. Engl. J. Med.

Polymorphism of the human beta3-adrenoceptor gene forms a well-conserved haplotype that is associated with moderate obesity and altered receptor function

Diabetes

Beta-adrenoceptor polymorphisms

Naunyn Schmiedebergs Arch. Pharmacol.

Adrenoceptor genes in human obesity

J. Intern. Med.

Association of BMI with the beta3-adrenergic receptor gene polymorphism in Japanese: meta-analysis

Obes. Res.

Meta-analysis of the association of the Trp64Arg polymorphism in the beta3 adrenergic receptor with insulin resistance

Obes. Res.

Beta 3-adrenergic-receptor polymorphism: a genetic marker for visceral fat obesity and the insulin resistance syndrome

Diabetologia

Review
Adrenergic receptor polymorphisms and autonomic nervous system function in human obesity

Association of α_2B-adrenergic receptor polymorphism with ANS function