Beta-2 adrenergic receptor variants are associated with subcutaneous fat accumulation in response to long-term overfeeding

Abstract

OBJECTIVE:The effects of alpha-2A (A2A)-, beta-2 (B2)-and beta-3 (B3)-adrenergic receptor (ADR) gene polymorphisms on adiposity, fat distribution and plasma insulin and leptin changes in response to long-term overfeeding were explored. METHODS: Twenty four men (mean ( AE s.d.) age 21 AE 2 y) who constituted 12 pairs of identical twins ate a 4.2 MJ=day energy surplus, 6 days a week, for a period of 100 days. Total body fat was assessed by hydrodensitometry and total subcutaneous fat by the sum of eight skinfolds. Abdominal fat areas were measured by computerized tomography (CT). Plasma glucose and insulin during fasting and in response to an oral glucose tolerance test (OGTT) were assayed. The insulin and glucose areas were computed using the trapezoidal method. Plasma leptin was measured with an enzyme-linked immunosorbent assay. The ADR polymorphisms were identified by PCR or Southern blot technique. RESULTS: The ADRB2 Gln27Gln genotype (n ¼ 10) was associated with a larger gain (percentage change) in weight (P < 0.001) and total subcutaneous (P < 0.005) fat than the Glu27Glu=Gln27Glu genotype (n ¼ 14). In addition, overfeeding induced greater increases in the insulin areas under the curve during the OGTT and the fasting plasma level of leptin (P < 0.01 and < 0.03, respectively) among Gln27Gln than in the Glu27Glu=Gln27Glu subjects. The body composition and metabolic changes among the ADRB2 BanI 3.7=3.4 kb subjects (n ¼ 10) were similar to those of Gln27Gln subjects. ADRA2A DraI (n ¼ 4) 6.3=6.3 kb subjects experienced a decrease (78%) while 6.7=6.3 kb subjects (n ¼ 20) registered an increase ( þ 10%; P ¼ 0.017) of OGTT glucose area after the 100-day caloric surplus. The four carriers of the ADRB3 variant (Trp64Arg) experienced the same magnitude of changes as the 20 homozygotes for the Trp allele. In general, comparisons based on the 24 subjects considered as unrelated men and the mean values for each of the 12 pairs yielded similar results. CONCLUSION: The ADRB2 Gln27Gln subjects gained more weight and total subcutaneous fatness and also experienced a greater increase in insulin resistance than Glu27Glu=Gln27Glu subjects with exposure to long-term overfeeding. Similar differences were observed between carriers and non-carriers of the ADRB2 3.7=3.4 kb BanI variant. Genetic variation at the ADRB2 locus could thus be one of the factors responsible for the large inter-individual differences observed in the response to long-term alterations in energy balance and should be further investigated.

Association of adipose tissue deposition and beta-2 adrenergic receptor variants: the IRAS family study

“…In a small study of 12 monozygotic male twin pairs, the Glu27 allele was associated with a greater increase in total CTmeasured subcutaneous fat and total weight gain in response to long-term overfeeding (Po0.005). 26 Two recent reports addressing the relationship between ADRB2 and fat measures quantified by CT from the HERITAGE study have produced evidence for association, but only in subgroups. The first 27 examined the Arg16Gly, but not the Gln27Glu, polymorphism with respect to response to endurance training in AA and Caucasian subjects, reporting no significant main-effect association between this polymorphism and change in CTmeasured visceral fat area, although they did report an interaction between Arg16Gly and a polymorphism in the beta-3 adrenergic receptor on change in total abdominal fat area.…”

“…Research investigating the relationship between ADRB2 and more direct measures of fat deposition, such as computed tomography (CT)-assessed visceral and subcutaneous fat mass, however, has been limited. A small twin study 26 and one report from the HERITAGE study 27 have provided some evidence of an effect of this gene on regional fat distribution. Both of these studies were interventional; however, with the first examining response to overfeeding and the second assessing response to endurance training.…”

Gln27Glu polymorphism in the beta2 adrenergic receptor gene and lipid metabolism during exercise in obese women

“…16 This is in line with our findings since lipolysis and fat oxidation during exercise were higher in our Gln27Gln group as compared to the Glu27Glu group, so again, the Gln27Gln genotype (lacking the Glu27 allele) seems to benefit more from exercise. Studies with identical twins would have provided clearer evidence, 39 but neither twins, nor siblings were found in our obese population, so homozygous Glu27Glu obese women were matched with other group of homozygous Gln27Gln women. This design has also been reported in similar studies.…”

Pharmacogenomics and nutrigenomics: synergies and differences

“…Even so, one genetic variation in the ADRB2 gene accounted for only about 7% of the variance 419 (differences) in weight gain in this study and the effect of other genetic variations was 420,421,422,423 smaller.…”