Polymorphisms in genes of leptin-melanocortin and insulin pathways have been associated with obesity and type 2 diabetes. We hypothesized that polymorphisms in IRS1, IRS2, MC3R, and MC4R influence metabolic and inflammatory markers and food intake composition in Brazilian subjects. This exploratory pilot study included 358 adult subjects. Clinical, anthropometric, and laboratory data were obtained through interview and access to medical records. The variants IRS1 rs2943634 A˃C, IRS2 rs1865434 C>T, MC3R rs3746619 C>A, and MC4R rs17782313 T>C were analyzed by real-time polymerase chain reaction. Food intake composition was assessed in a group of subjects with obesity (n = 84) before and after a short-term nutritional counseling program (9 weeks). MC4R rs17782313 was associated with increased risk of obesity (P = .034). Multivariate linear regression analysis adjusted by covariates indicated associations of IRS2 rs1865434 with reduced low-density lipoprotein cholesterol and resistin, MC3R rs3746619 with high glycated hemoglobin, and IRS1 rs2943634 and MC4R rs17782313 with increased high-sensitivity C-reactive protein (P < .05). Energy intake and carbohydrate and total fat intakes were reduced after the diet-oriented program (P < .05). Multivariate linear regression analysis showed associations of IRS2 rs1865434 with high basal fiber intake, IRS1 rs2943634 with low postprogram carbohydrate intake, and MC4R rs17782313 with low postprogram total fat and saturated fatty acid intakes (P < .05). Although significant associations did not survive correction for multiple comparisons using the Benjamini-Hochberg method in this exploratory study, polymorphisms in IRS1, IRS2, MC3R, and MC4R influence metabolic and inflammatory status in Brazilian adults. IRS1 and MC4R variants may influence carbohydrate, total fat, and saturated fatty acid intakes in response to a diet-oriented program in subjects with obesity. Clinical, anthropometric, and laboratory data were obtained from 358 Brazilian adult subjects. IRS1 rs2943634, IRS2 rs1865434, MC3R rs3746619, and MC4R rs17782313 polymorphisms were evaluated. Food intake composition was assessed in 84 subjects with obesity before and after a short-term nutritional counseling program. Variants in IRS1, IRS2, MC3R, and MC4R influence metabolic and inflammatory status. IRS1 and MC4R variants may influence carbohydrate, total fat, and saturated fatty acids intakes in response to a diet-oriented program. Abbreviations: HbA1c, glycated hemoglobin; hsCRP, high-sensitivity C-reactive protein; InsR, insulin receptor; IRS1, insulin receptor substrate 1; IRS2, insulin receptor substrate 2; LDL-c, low-density lipoprotein cholesterol; LepR, leptin receptor; MC3R, melanocortin receptor 3; MC4R, melanocortin receptor 4; SFA, saturated fatty acids; 9w, 9 weeks. Display omitted