Association analyses of adrenergic receptor polymorphisms with obesity and metabolic alterations
Introduction
Obesity is a major health problem in the United States. Sixty-five percent of American adults are overweight, and more than 30% are obese [1]. It is well accepted that obesity in some, but not in all, individuals leads to metabolic alterations including hyperinsulinemia and insulin resistance [2], which can lead to the development of type 2 diabetes mellitus and to cardiovascular diseases and some forms of cancer [3], [4], [5], [6]. Although rare, obesity syndromes can be caused by mutations in single genes. However, the greatest proportion of obesity involves variants in multiple genes interacting with environmental factors, particularly diet [7], [8].
Genes that are involved in the regulation of catecholamine function may be important in obesity because of the role catecholamines play in energy expenditure and lipolysis. Fat stored in the body as triglycerides is hydrolyzed to free fatty acids and glycerol through the process of lipolysis [9]. Activation of β-adrenergic receptors (ADRBs) expressed in adipocytes mediate lipolysis [3], [10], [11], whereas stimulation of α2-adrenergic receptors (ADRA2) inhibit lipolysis [12]. Insulin is also an important inhibitor of catecholamine-stimulated lipolysis [13] by reducing the ADBR effects of epinephrine and by activating ADRA2 in adipocytes [14].
In addition, catecholamine-stimulated whole-body lipolysis and lipolysis in subcutaneous adipocytes are blunted in obesity [10], [15], [16], thereby limiting lipid mobilization and favoring fat accumulation. The mechanisms underlying lipolytic resistance to catecholamines in obesity are not clear and may include desensitization of ADRB2 function [17], increased activity of ADRA, and the hyperinsulinemia that accompanies obesity [18], [19].
Several mutations in genes encoding ADRA and ADRB have been identified that could alter receptor expression and function. Given the important role that adrenergic receptors play in regulating energy expenditure and lipolysis, it is possible that common genetic polymorphisms in these genes contribute to obesity and to the accompanying metabolic alterations. Numerous studies have reported on the relationship between obesity and genetic variants in adrenergic receptors in different populations with conflicting results [20], [21], [22]. Few, however, have explored associations between adrenergic receptor polymorphisms and obesity and accompanying metabolic alterations in self-identified African Americans and whites. In the present study we tested the hypothesis that obesity and metabolic alterations associate with common polymorphisms in adrenergic receptor genes.
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Study participants and outcome measures
All participants were between the ages of 18 and 49 years, healthy, nonsmokers, and were not taking any medications chronically. Body mass index (BMI) was calculated from height and weight using the formula: BMI = [body weight (pounds)/height (inches)2] × 704.5. Obesity was defined as a BMI of 30 or more [1]. Percentage of body fat was determined by calculating the mean of 3 measurements of skinfold thickness in 7 different anatomical sites (triceps, biceps, subscapula, abdominal, suprailiac,
Participants
A total of 238 subjects participated in the study; 161 were self-identified whites (7 Hispanic, 154 non-Hispanic), 74 were African Americans, and the remaining participants were either Indian (2) or Asian (1). Because of the small numbers of Indians and Asians, analyses were performed on 235 participants; 161 self-identified whites (72.7% female) and 74 African Americans (80% female). Mean age ± SD for African Americans and whites were 30 ± 8.7 vs 30 ± 8.0 years, respectively (P = .63). Among
Discussion
Obesity is a common complex disease that involves multiple genetic variants interacting with environmental and behavioral factors. Genes involved in the regulation of catecholamine function may be important in obesity because of the role catecholamines play in energy expenditure and lipolysis. Stimulation of ADRB increases lipolysis, which favors weight reduction, whereas ADRA2A inhibits lipolysis, which favors weight gain. In the present study we hypothesized that common SNPs in ADRB and ADRA2A
Acknowledgment
This work was supported by NIH grant R03DK57734.
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