Appetite regulatory neural network and adipocyte homeostasis molecular pathways are critical to long-term weight maintenance. Associations between obesity-related phenotypes and four genes in these pathways - leptin (LEP), leptin receptor (LEPR), neuropeptide Y2 receptor (NPY2R) and peptide YY (PYY) were examined in CARDIA Study participants (aged 18-30 at recruitment in 1985-6). Weight, BMI and waist circumference were measured at baseline and at years 2, 5, 7, 10, 15, and 20. Genotyping was conducted using tag SNPs characterising common genetic variations in these genes. Generalized estimating equation (GEE) models estimated associations between SNPs and repeated anthropometric measurements, controlling for sex and age. False discovery rate was used to adjust for multiple testing. In African-Americans, SNPs across the LEP gene demonstrated significant overall associations with all obesity-related phenotypes. The associations between LEP rs17151919 with weight tended to strengthen with time - the difference in weight associated with each additional minor allele increased from 2.6 kg at baseline to 4.8 kg at year 20 (SNP*time interaction p = 0.0193). NPY2R gene SNPs were associated with waist circumference among African-American men (p = 0.0462). In Caucasians, LEP SNPs also tended to be associated with weight (p = 0.0471), and PYY rs11684664 was associated with obesity-related phenotypes in women only (p = 0.010-0.026).Several LEP, and NPY2R and PYY SNPs were associated with obesity-related phenotypes in young adults, particularly among African-Americans. © 2010 The Authors Annals of Human Genetics © 2010 Blackwell Publishing Ltd/University College London.