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

OBJECTIVE: The effects of alpha-2A (A2A)-, beta-2 (B2)- and beta-3 (B3)-adr energic receptor (ADR) gene polymorphisms on adiposity, fat distribution an d plasma insulin and leptin changes in response to long-term overfeeding we re explored. METHODS: Twenty four men (mean ( +/- s.d.) age 21 +/- 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 ar eas were measured by computerized tomography (CT). Plasma glucose and insul in during fasting and in response to an oral glucose tolerance test (OGTT) were assayed. The insulin and glucose areas were computed using the trapezo idal method. Plasma leptin was measured with an enzyme-linked immunosorbent assay. The ADR polymorphisms were identified by PCR or Southern blot techn ique. RESULTS: The ADRB2 Gln27Gln genotype (n = 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 = 14). In addition, overf eeding induced wgreater increases in the insulin areas under the curve duri ng the OGTT and the fasting plasma level of leptin (P < 0.01 and < 0.03, re spectively) 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 = 10) were similar to those of Gln27Gln subjects. ADRA2A Dral (n = 4) 6 .3/6.3 kb subjects experienced a decrease (- 8%) while 6.7/6.3 kb subjects (n = 20) registered an increase ( + 10%; P = 0.017) of OGTT glucose area af ter the 100-day caloric surplus. The four carriers of the ADRB3 variant (Tr p64Arg) experienced the same magnitude of changes as the 20 homozygotes for the Trp allele. In general, comparisons based on the 24 subjects considere d as unrelated men and the mean values for each of the 12 pairs yielded sim ilar results. CONCLUSION: The ADRB2 Gln27Gln subjects gained more weight and total subcut aneous fatness and also experienced a greater increase in insulin resistanc e than Glu27Glu/Gln27Glu subjects with exposure to long-term overfeeding. S imilar differences were observed between carriers and non-carriers of the A DRB2 3.7/3.4 kb BanI variant. Genetic variation at the ADRB2 locus could th us be one of the factors responsible for the large inter-individual differe nces observed in the response to long-term alterations in energy balance an d should be further investigated.