*109691	Links
BETA-3-ADRENERGIC RECEPTOR; ADRB3

Gene map locus 8p12-p11.2

TEXT

CLONING

Emorine et al. (1989) isolated a third beta-adrenergic receptor, beta-3-adrenergic receptor (ADRB3). (See ADRB1 (109630) and ADRB2 (109690).) Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promoted the accumulation of adenosine 3-prime,5-prime-monophosphate. The potency of beta-AR agonists and inhibitors was described.

Van Spronsen et al. (1993) demonstrated that the transcription start sites of the mouse and human ADRB3 mRNA are located in a region comprised between 150 and 200 nucleotides 5-prime from the ATG translation start codon. Motifs potentially implicated in heterologous regulation of ADRB3 expression by glucocorticoids and by beta-adrenergic agonists were identified upstream from these cap sites.

GENE STRUCTURE

Van Spronsen et al. (1993) described the exon/intron structure of the mouse and human ADRB3 genes. Their results suggested that utilization of alternate promoters and/or 3-prime untranslated regions may allow tissue-specific regulation of the expression of ADRB3.

MAPPING

Wilkie et al. (1993) presented a list of G protein-coupled receptor genes (their Table 3), indicating that the ADRB3 gene had been mapped to 8p12-p11.2 and the homologous gene to mouse chromosome 8.

MOLECULAR GENETICS

The beta-3-adrenergic receptor, located mainly in adipose tissue, is involved in the regulation of lipolysis and thermogenesis. The potential relevance of this receptor to obesity (see 601665) in humans led Clement et al. (1995) to screen obese patients for the mutation in the ADRB3 gene that results in replacement of tryptophan by arginine at position 64 (W64R; 109691.0001). They studied DNA extracted from leukocytes of 94 normal subjects and 185 unrelated patients with morbid obesity, as defined by a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) greater than 40. The mutation was detected by analysis of RFLPs with the restriction enzyme BstNI, which discriminates between the normal and mutant sequences. The frequency of the W64R variant was similar in the morbidly obese patients and the normal subjects: 0.08 and 0.10, respectively. However, patients with morbid obesity who were heterozygous for the allele had an increased capacity to gain weight: the mean weight in the 14 heterozygous patients was 140 kg, as compared with 126 kg in the 171 patients without the mutation (P = 0.03). There were no homozygotes in this sample. The cumulative 25-year change in weight (from the age of 20 years) was 67 kg in W64R heterozygotes, as compared with 51 kg in those without the mutation. The maximum weight differential (the maximal lifetime weight minus the weight at 20 years of age) in the heterozygotes was 74 kg, as compared with 59 kg in the patients without the mutation (P = 0.02). Clement et al. (1995) interpreted the findings as indicating that the ADRB3 gene mutation W64R increases the capacity to gain weight.

ANIMAL MODEL

To determine whether the sympathetic nervous system is the efferent arm of diet-induced thermogenesis, Bachman et al. (2002) created mice that lacked the beta-adrenergic receptors ADRB1, ADRB2, and ADRB3. Beta-less mice on a chow diet had a reduced metabolic rate and were slightly obese. On a high-fat diet, beta-less mice, in contrast to wildtype mice, developed massive obesity that was due entirely to a failure of diet-induced thermogenesis. Bachman et al. (2002) concluded that the beta-adrenergic receptors are necessary for diet-induced thermogenesis and that this efferent pathway plays a critical role in the body's defense against diet-induced obesity.

ALLELIC VARIANTS
(selected examples)

.0001 OBESITY, SUSCEPTIBILITY TO [ADRB3, TRP64ARG]

Using a candidate gene approach to study the genetics of obesity (601665), Clement et al. (1995) found evidence suggesting that the trp64-to-arg (W64R) variant of the ADRB3 gene increases the capacity to gain weight. Gagnon et al. (1996) failed to find an association between W64R and obesity in studies in 2 cohorts: the Quebec Family Study (QFS) and the Swedish Obese Subjects (SOS).

Walston et al. (1995) found that Pima Indians homozygous for the W64R ADRB3 mutation had an earlier onset of noninsulin-dependent diabetes mellitus (NIDDM; 125853) and tended to have a lower resting metabolic rate. The authors suggested that the mutation may accelerate the onset of NIDDM by altering the balance of energy metabolism in visceral adipose tissue.

Elbein et al. (1996) tested the hypothesis that the beta-3-adrenergic receptor locus affects diabetes susceptibility, obesity as measured by body mass index (BMI), and components of the insulin (176730) resistance syndrome, by examining ADRB3 allele sharing in families ascertained for 2 or more sibs with NIDDM. They found no evidence for linkage to NIDDM as a dichotomous trait and no evidence for linkage to BMI, waist/hip ratio, insulin levels, or glucose levels as quantitative traits or to reported age of onset among NIDDM individuals. The W64R mutation present in 11% of the population also did not show linkage or association. They concluded that the beta-3-adrenergic receptor locus does not play an important role in NIDDM susceptibility or in the insulin resistance syndrome among members of families with a strong predisposition to NIDDM.

Kim-Motoyama et al. (1997) examined the frequency of the W64R variant in 278 Japanese men in relation to visceral obesity assessed by computerized tomography. They found that the mutation was more frequent in subjects with higher BMI. In subjects with a moderate degree of obesity, the mutation (homozygotes and heterozygotes) was associated with visceral obesity (higher ratio of visceral to subcutaneous fat area). Furthermore, the W64R variant was more frequent in subjects with lower serum triglyceride levels, and homozygotes, but not heterozygotes, exhibited lower triglyceride levels. Kim-Motoyama et al. (1997) suggested that the mutation may describe a subset of subjects characterized by decreased lipolysis in visceral adipose tissue.

To examine the effect of W64R on body weight during adult life, the ADRB3 genotypes of 186 unselected Japanese men, most of whom had records of body weight measured yearly from 25 to 53 years of age, were determined by Nagase et al. (1997). Of these subjects, 26 were diagnosed as having noninsulin-dependent diabetes mellitus (NIDDM) and 41 as having impaired glucose tolerance. The results suggested that ADRB3 is not a major contributing factor to obesity or NIDDM in Japanese men.

Buettner et al. (1998) examined the prevalence of the 2 ADRB3 alleles in Germany and looked for associations between the ADRB3 genotype and obesity and NIDDM. The frequencies of the different genotypes in the examined cohort were as follows: trp64/trp64, 88.3%; trp64/arg64, 10.8%; and arg64/arg64, 0.8%. The authors found no significant differences between the different genotypes when comparing age, BMI, weight, total and high density lipoprotein, cholesterol, fasting insulin, HbA1c, and blood pressure. They concluded that the NIDDM phenotype did not differ significantly between the different genotype groups in terms of age of diabetes onset or HbA1c.

Using hyperinsulinemic/euglycemic clamp methodology, Garcia-Rubi et al. (1998) measured insulin sensitivity in 13 obese women heterozygous for the W64R ADRB3 variant and in 14 women homozygous for the normal gene. Exogenous glucose infusion during the clamp was significantly lower (P = 0.03) in W64R heterozygotes (241 +/- 135 mg/min) compared with normal homozygotes (379 +/- 172 mg/min). They concluded that obese postmenopausal women who are heterozygous for the W64R variant have greater insulin resistance than women homozygous for the normal gene matched for age, body composition, and physical activity.

Mitchell et al. (1998) detected an effect of the W64R variant on obesity in a Mexican-American population. They had previously identified a major quantitative trait locus (QTL) influencing the serum concentrations of leptin on 2p in a Mexican-American population in south Texas (Comuzzie et al., 1997). They studied 45 sib pairs who were concordant (identical by descent) for this locus on chromosome 2, which had been shown previously to be tightly linked to obesity in this population. The W64R variant, detected by PCR-RFLP analysis, was present in 1 sib within each of the 45 sib pairs. Presence of the variant was associated with a significantly higher values in body mass index, fat mass, and waist circumference. The paired-sib design enhanced their ability to detect the effects of this variant by allowing them to account for variation attributable to another obesity susceptibility locus and to background genes.

Since ADRB3 plays a significant role in the control of lipolysis and thermogenesis in brown adipose tissue through autonomic nervous system (ANS) activity, Shihara et al. (1999) investigated the association of the W64R polymorphism with ANS activity. Subjects with the polymorphism did not differ from subjects without it in BMI, plasma glucose, plasma insulin, or family history of diabetes or obesity. The total power of heterozygotes at supine rest was lower than that of normal subjects (1,124.6 +/- 191.6 vs 3,029.8 +/- 758.8 ms2; mean +/- SE). With a postural change to standing, the parasympathetic and sympathetic nervous system activity indexes of heterozygotes showed a higher response than those of normal subjects (parasympathetic nervous system index, 0.10 +/- 0.02 vs 0.17 +/- 0.02; sympathetic nervous system index, 10.55 +/- 1.47 vs 6.26 +/- 1.09) and the difference in total power disappeared. The authors concluded that subjects with the polymorphism, even heterozygotes, had lower resting ANS activity than did normal subjects.

Hoffstedt et al. (1999) studied 208 healthy Swedish subjects. Twenty-two percent of those with a high BMI (defined as greater than 31 kg/m(2)) carried the W64R ADRB3 variant, compared with 11% of those who had a lower BMI. Furthermore, BMI was approximately 2 kg/m(2) higher in arg carriers compared with subjects who were trp homozygous in the lower BMI group. No association of the W64R haplotype with metabolic parameters or blood pressure was identified. When comparing sensitivity for CPG12177, a selective beta-3-receptor agonist, Hoffstedt et al. (1999) observed a 10-fold decrease in beta-3-arg compared with beta-3-trp subjects.

Festa et al. (1999) studied the relationship between ADRB3 genotype and glucose tolerance during pregnancy, a state of physiologic insulin resistance. The frequency of the W64R allele was 9.15% in 179 pregnant women. In 70 women with mild gestational diabetes, as defined by 60-minute postload glucose values, the W64R genotype was more frequent than in 109 women with normal glucose tolerance (26% vs 11%; P of 0.01). Furthermore, the W64R genotype was associated with increased weight gain during pregnancy (baseline to gestational weeks 20 to 31) and increased postload glucose, insulin, and C peptide values during the oral glucose tolerance test. This apparent association with mild gestational diabetes suggested to the authors that the impact of the polymorphism may be clinically important during pregnancy.

The study of Urhammer et al. (2000) failed to demonstrate an additive or synergistic effect of the W64R variant of the ADRB3 gene and the -3826 A-G variant of the UCP1 gene (113730.0001) on the development of obesity and insulin resistance among randomly recruited Danish Caucasian subjects.

Walston et al. (2000) found that arg64/arg64 homozygotes secrete significantly less insulin in response to a glucose infusion, have higher fasting glucose levels, and have lower glucose effectiveness compared with trp64/trp64 homozygotes. They concluded that their data may help explain the earlier onset of type 2 diabetes mellitus (NIDDM) observed in several populations of individuals with the arg64 ADRB3 variant allele.

Wang et al. (2004) evaluated whether the W64R polymorphism in the ADRB3 gene is associated with decreased birth weight and might account for some of the association between birth weight and impaired insulin sensitivity. Frequency of the W64R allele was similar in groups of neonates classified as appropriate for gestational age (AGA) and small for gestational age (SGA) (0.15 and 0.17, respectively). Moreover, after adjustment for sex and gestational age, there was no significant difference in birth weight, fasting glucose, insulin levels, or insulin-to-glucose ratio between those with and without the mutation. However, in the SGA group, carriers of the W64R allele had significantly higher fasting insulin levels and insulin-to-glucose ratios than noncarriers, whereas no association was detected for this polymorphism in the AGA group.

REFERENCES

1. Bachman, E. S.; Dhillon, H.; Zhang, C.-Y.; Cinti, S.; Bianco, A. C.; Kobilka, B. K.; Lowell, B. B. :

Beta-AR signaling required for diet-induced thermogenesis and obesity resistance. Science 297: 843-845, 2002.
PubMed ID : 12161655

2. Buettner, R.; Schaffler, A.; Arndt, H.; Rogler, G.; Nusser, J.; Zietz, B.; Enger, I.; Hugl, S.; Cuk, A.; Scholmerich, J.; Palitzsch, K.-D. :

The trp64arg polymorphism of the beta-3-adrenergic receptor gene is not associated with obesity or type 2 diabetes mellitus in a large population-based Caucasian cohort. J. Clin. Endocr. Metab. 83: 2892-2897, 1998.
PubMed ID : 9709965

3. Clement, K.; Vaisse, C.; Manning, B. S. J.; Basdevant, A.; Guy-Grand, B.; Ruiz, J.; Silver, K. D.; Shuldiner, A. R.; Froguel, P.; Strosberg, A. D. :

Genetic variation in the beta-3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. New Eng. J. Med. 333: 352-354, 1995.
PubMed ID : 7609752

4. Comuzzie, A. G.; Hixson, J. E.; Almasy, L.; Mitchell, B. D.; Mahaney, M. C.; Dyer, T. D.; Stern, M. P.; MacCluer, J. W.; Blangero, J. :

A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nature Genet. 15: 273-276, 1997.
PubMed ID : 9054940

5. Elbein, S. C.; Hoffman, M.; Barrett, K.; Wegner, K.; Miles, C.; Bachman, K.; Berkowitz, D.; Shuldiner, A. R.; Leppert, M. F.; Hasstedt, S. :

Role of the beta-3-adrenergic receptor locus in obesity and noninsulin-dependent diabetes among members of Caucasian families with a diabetic sibling pair. J. Clin. Endocr. Metab. 81: 4422-4427, 1996.
PubMed ID : 8954053

6. Emorine, L. J.; Marullo, S.; Briend-Sutren, M.-M.; Patey, G.; Tate, K.; Delavier-Klutchko, C.; Strosberg, A. D. :

Molecular characterization of the human beta-3-adrenergic receptor. Science 245: 1118-1121, 1989.
PubMed ID : 2570461

7. Festa, A.; Krugluger, W.; Shnawa, N.; Hopmeier, P.; Haffner, S. M.; Schernthaner, G. :

Trp64Arg polymorphism of the beta-3-adrenergic receptor gene in pregnancy: association with mild gestational diabetes mellitus. J. Clin. Endocr. Metab. 84: 1695-1699, 1999.
PubMed ID : 10323402

8. Gagnon, J.; Mauriege, P.; Roy, S.; Sjostrom, D.; Chagnon, Y. C.; Dionne, F. T.; Oppert, J.-M.; Perusse, L.; Sjostrom, L.; Bouchard, C. :

The trp64arg mutation of the beta-3 adrenergic receptor gene has no effect on obesity phenotypes in the Quebec Family Study and Swedish Obese Subjects cohorts. J. Clin. Invest. 98: 2086-2093, 1996.
PubMed ID : 8903328

9. Garcia-Rubi, E.; Starling, R. D.; Tchernof, A.; Matthews, D. E.; Walston, J. D.; Shuldiner, A. R.; Silver, K.; Poehlman, E. T.; Calles-Escandon, J. :

Trp64Arg variant of the beta-3-adrenoceptor and insulin resistance in obese postmenopausal women. J. Clin. Endocr. Metab. 83: 4002-4005, 1998.
PubMed ID : 9814483

10. Hoffstedt, J.; Poirier, O.; Thorne, A.; Lonnqvist, F.; Herrmann, S. M.; Cambien, F.; Arner, P. :

Polymorphism of the human beta-3-adrenoceptor gene forms a well-conserved haplotype that is associated with moderate obesity and altered receptor function. Diabetes 48: 203-205, 1999.
PubMed ID : 9892244

11. Kim-Motoyama, H.; Yasuda, K.; Yamaguchi, T.; Yamada, N.; Katakura, T.; Shuldiner, A. R.; Akanuma, Y.; Ohashi, Y.; Yazaki, Y.; Kadowaki, T. :

A mutation of the beta-3-adrenergic receptor is associated with visceral obesity but decreased serum triglyceride. Diabetologia 40: 469-472, 1997.
PubMed ID : 9112025

12. Mitchell, B. D.; Blangero, J.; Comuzzie, A. G.; Almasy, L. A.; Shuldiner, A. R.; Silver, K.; Stern, M. P.; MacCluer, J. W.; Hixson, J. E. :

A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans. J. Clin. Invest. 101: 584-587, 1998.
PubMed ID : 9449691

13. Nagase, T.; Aoki, A.; Yamamoto, M.; Yasuda, H.; Kado, S.; Nishikawa, M.; Kugai, N.; Akatsu, T.; Nagata, N. :

Lack of association between the trp64arg mutation in the beta-3-adrenergic receptor gene and obesity in Japanese men: a longitudinal analysis. J. Clin. Endocr. Metab. 82: 1284-1287, 1997.
PubMed ID : 9100608

14. Shihara, N.; Yasuda, K.; Moritani, T.; Ue, H.; Adachi, T.; Tanaka, H.; Tsuda, K.; Seino, Y. :

The association between Trp64Arg polymorphism of the beta-3-adrenergic receptor and autonomic nervous system activity. J. Clin. Endocr. Metab. 84: 1623-1627, 1999.
PubMed ID : 10323390

15. Urhammer, S. A.; Hansen, T.; Borch-Johnsen, K.; Pedersen, O. :

Studies of the synergistic effect of the trp/arg64 polymorphism of the beta-3-adrenergic receptor gene and the -3826 A-G variant of the uncoupling protein-1 gene on features of obesity and insulin resistance in a population-based sample of 379 young Danish subjects. J. Clin. Endocr. Metab. 85: 3151-3154, 2000.
PubMed ID : 10999801

16. Van Spronsen, A.; Nahmias, C.; Krief, S.; Briend-Sutren, M.-M.; Strosberg, A. D.; Emorine, L. J. :

The promoter and intron/exon structure of the human and mouse beta-3-adrenergic-receptor genes. Europ. J. Biochem. 213: 1117-1124, 1993.
PubMed ID : 8389293

17. Walston, J.; Silver, K.; Bogardus, C.; Knowler, W. C.; Celi, F. S.; Austin, S.; Manning, B.; Strosberg, A. D.; Stern, M. P.; Raben, N.; Sorkin, J. D.; Roth, J.; Shuldiner, A. R. :

Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta-3-adrenergic-receptor gene. New Eng. J. Med. 333: 343-347, 1995.
PubMed ID : 7609750

18. Walston, J.; Silver, K.; Hilfiker, H.; Andersen, R. E.; Seibert, M.; Beamer, B.; Roth, J.; Poehlman, E.; Shuldiner, A. R. :

Insulin response to glucose is lower in individuals homozygous for the arg64 variant of the beta-3-andrenergic receptor. J. Clin. Endocr. Metab. 85: 4019-4022, 2000.
PubMed ID : 11095426

19. Wang, X.; Cui, Y.; Tong, X.; Ye, H.; Li, S. :

Effects of the trp64arg polymorphism in the beta-3-adrenergic receptor gene on insulin sensitivity in small for gestational age neonates. J. Clin. Endocr. Metab. 89: 4981-4985, 2004.
PubMed ID : 15472194

20. Wilkie, T. M.; Chen, Y.; Gilbert, D. J.; Moore, K. J.; Yu, L.; Simon, M. I.; Copeland, N. G.; Jenkins, N. A. :

Identification, chromosomal location, and genome organization of mammalian G-protein-coupled receptors. Genomics 18: 175-184, 1993.
PubMed ID : 8288218

CONTRIBUTORS

John A. Phillips, III - updated : 10/26/2005
Ada Hamosh - updated : 8/7/2002
John A. Phillips, III - updated : 8/9/2001
John A. Phillips, III - updated : 3/16/2001
John A. Phillips, III - updated : 3/20/2000
Ada Hamosh - updated : 5/18/1999
John A. Phillips, III - updated : 3/19/1999
John A. Phillips, III - updated : 3/3/1999
Victor A. McKusick - updated : 3/31/1998
Victor A. McKusick - updated : 3/25/1998
Victor A. McKusick - updated : 8/7/1997
John A. Phillips, III - updated : 4/17/1997
John A. Phillips, III - updated : 12/20/1996

CREATION DATE

Victor A. McKusick : 12/14/1993

EDIT HISTORY

alopez : 10/26/2005
carol : 6/1/2005
alopez : 8/8/2002
terry : 8/7/2002
alopez : 8/9/2001
alopez : 3/16/2001
mgross : 4/12/2000
terry : 3/20/2000
alopez : 5/25/1999
terry : 5/18/1999
mgross : 3/23/1999
mgross : 3/19/1999
mgross : 3/11/1999
mgross : 3/3/1999
dkim : 12/11/1998
psherman : 3/31/1998
terry : 3/26/1998
alopez : 3/25/1998
terry : 3/20/1998
terry : 8/11/1997
terry : 8/7/1997
terry : 8/7/1997
alopez : 7/30/1997
alopez : 7/30/1997
alopez : 7/9/1997
jenny : 5/21/1997
jenny : 5/21/1997
jenny : 5/21/1997
jenny : 5/21/1997
jenny : 12/12/1996
terry : 12/6/1996
mark : 2/22/1996
terry : 2/19/1996
mark : 9/7/1995
carol : 12/14/1993

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