Genetic Variation in the Peroxisome Proliferator–Activated Receptor-γ2 Gene (Pro12Ala) Affects Metabolic Responses to Weight Loss and Subsequent Weight Regain

Genetic Variation in the Peroxisome Proliferator–Activated Receptor-γ2 Gene (Pro12Ala) Affects Metabolic Responses to Weight Loss and Subsequent Weight Regain Barbara J. Nicklas 1 , Elisabeth F.C. van Rossum 1 , Dora M. Berman 1 , Alice S. Ryan 1 , Karen E. Dennis 1 and Alan R. Shuldiner 2 1 Division of Gerontology and Endocrinology, University of Maryland School of Medicine, Department of Medicine, Baltimore V.A. Medical Center, Baltimore, Maryland, and the 2 Division of Diabetes and Nutrition, University of Maryland School of Medicine, Department of Medicine, Baltimore V.A. Medical Center, Baltimore, Maryland Abstract This study determined the effects of the peroxisome proliferator–activated receptor (PPAR)-γ2 Pro12Ala variant on body composition and metabolism and the magnitude of weight regain in 70 postmenopausal women (BMI 25–40 kg/m 2 ) who completed 6 months of a hypocaloric diet. At baseline, BMI, percent body fat, intra-abdominal and subcutaneous abdominal fat areas, resting metabolic rate, substrate oxidation, and postprandial glucose and insulin responses were not different between genotypes (Pro/Pro = 56, Pro/Ala and Ala/Ala = 14). The intervention similarly decreased body weight by 8 ± 1% in women homozygous for the Pro allele and by 7 ± 1% in women with the Ala allele ( P < 0.0001). Fat oxidation did not change in Pro/Pro women but decreased 19 ± 9% in women with the Ala allele ( P < 0.05). Changes in glucose area were not different between groups; however, women with the Ala allele decreased their insulin area more than women homozygous for the Pro allele ( P < 0.05). Weight regain during follow-up was greater in women with the Ala allele than women homozygous for the Pro allele (5.4 ± 0.9 vs. 2.8 ± 0.4 kg, P < 0.01). PPAR-γ2 genotype was the best predictor of weight regain ( r = 0.50, P < 0.01), followed by the change in fat oxidation (partial r = 0.35, P < 0.05; cumulative r = 0.58). Thus, the Pro12Ala variant of the PPAR-γ2 gene may influence susceptibility for obesity. Footnotes Address correspondence and reprint requests to Barbara J. Nicklas, PhD, Division of Gerontology, Baltimore V.A. Medical Center, 10 N. Greene St., Baltimore, MD 21201. E-mail: bnicklas{at}umaryland.edu . Received for publication 31 October 2000 and accepted in revised form 15 June 2001. PPAR, peroxisome proliferator–activated receptor; RMR, resting metabolic rate.