Genetic variation at the uncoupling protein 1, 2 and 3 loci and the response to long-term overfeeding

Objective: To evaluate the effects of uncoupling protein (UCP) 1, UCP2 and UCP3 gene variants on body composition and metabolic changes in response to chronic overfeeding and the recovery after the period of overfeeding. Subjects and design: Twenty-four normal weight men (21 +/- 2 y), who consti tuted 12 pairs of identical twins, ate a 4.2 MJ/day energy surplus, 6 days a week, during a period of 100 days. The subjects were asked to return to t he laboratory for testing at 4 months and for a final examination 5 y after completion or tile overfeeding protocol. Methods: Resting metabolic rate (RMR) measurements were performed before an d after overfeeding. A 4,2 MJ test meal was consumed, after which calorimet ric measurements were continued for 240 min. Total body fat was assessed by hydrodensitometry and total subcutaneous fat by the sum of eight skinfolds . Polymorphisms were typed by PCR and PCR-RFLP-techniques. Thyroid stimulat ing hormone (TSH) concentrations after a thyrotropin releasing hormone (TRH ) injection were measured by radioimmunoassay (RIA). Results: The changes in body weight and adiposity were not different betwee n UCP1 Bcl 1, UCP2 alanine to valine (A55V), UCP2 insertion/deletion (I/D) or UCP3 Rsa I genotypes. However, the recovery from overfeeding was worse a mong G-allele carriers of the UCP1 Bcl 1, 1 allele non-carriers of the UCP2 I/D, AV heterozygote subjects of the UCP2 A55V and CC subjects of the UCP3 Rsa I polymorphisms. RMR was lower both before (P = 0.01) and after (P = 0 .001) overfeeding in subjects with the CC genotype of the UCP3 Rsa I polymo rphism. Moreover, after overfeeding, the UCP2 A55V heterozygote and UCP3 Rs a I CC homozygote subjects had significantly higher respiratory quotient (R Q) values at rest (P < 0.01) and during the meal test (P from < 0.01 to < 0 .05). Also mean plasma TSH concentrations 20, 30 and 45 min after the TRH i njection increased more with overfeeding among UCP2 A55V (P < 0.005) and UC P3 Rsa I CC (P = 0.017) subjects. Conclusions: These data suggest that UCP polymorphisms may play a role in t ile recovery from tile overfeeding by regulating substrate oxidation in res ponse to long-term caloric surplus. The association of the UCP2 A55V and UC P3 Rsa I CC genotypes with a greater increase in the TSH response to TRH lo ad could reflect a compensatory mechanism counteracting the effects of over feeding. A longer period or exposure to chronic positive energy balance con ditions may be necessary before sequence variation in UCP2 and UCP3 makes a n impact on thyroid metabolism to influence body mass and composition chang es.