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Identification of a Three-Amino Acid Deletion in the _2B-Adrenergic Receptor That Is Associated with Reduced Basal Metabolic Rate in Obese Subjects

Department of Pharmacology and Clinical Pharmacology, University of Turku (P.H., M.K., U.P., M.K.K., M.S.), FIN-20520 Turku; the Eating Disorder Unit, University Hospital of Helsinki (A.R.), FIN-00250 Helsinki; and the Departments of Medicine (M.L.) and Clinical Nutrition (R.V., M.U.), University of Kuopio, FIN-70211 Kuopio, Finland

Address all correspondence and requests for reprints to: Dr. Markku Koulu, Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. E-mail: markku.koulu{at}utu.fi

The ₂-adrenergic receptors mediate part of the actions of the catecholamines noradrenaline and adrenaline on the regulation of energy balance. As part of an ongoing study on the genetics of obesity, the entire coding sequence of the _2B-adrenoceptor gene was screened in 58 obese, nondiabetic Finns by PCR-single stranded conformational analysis (PCR-SSCA). A polymorphism that leads to a deletion of 3 glutamic acids from a glutamic acid repeat element (Glu x 12, amino acids 297–309) present in the third intracellular loop of the receptor protein was identified. This repeat element has previously been shown to be important for agonist-dependent receptor desensitization. Of 166 genotyped subjects, 47 (28%) had 2 normal (long) alleles (Glu¹²/Glu¹²), 90 (54%) were heterozygous (Glu¹²/Glu⁹), and 29 (17%) were homozygous for the short (Glu⁹/Glu⁹) form. The basal metabolic rate, determined by indirect calorimetry and adjusted for fat-free body mass, fat mass, sex, and age, was 94 Cal/day (5.6%) lower (95% confidence interval for difference, 32, 156) in subjects homozygous for the short allele than in subjects with two long alleles (F = 4.84; P = 0.009, by ANOVA). Thus, a genetic polymorphism of the _2B-adrenoceptor subtype can partly explain the variation in basal metabolic rate in an obese population and may therefore contribute to the pathogenesis of obesity.

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