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BackgroundObesity is a risk factor for insulin resistance (IR) and metabolic disease.ObjectiveTo examine potential metabolic pathways linking childhood weight status to adolescent IR and metabolic risk.MethodsParticipants were 600 low- to middle-income Chilean adolescents from a cohort studied since infancy as part of an iron deficiency anemia preventive trial and follow-up study. We examined body mass index z-score at 10 y (BMIz-10y) and blood pressure, total fat, and fasting glucose, adiponectin to leptin ratio (A:L), ghrelin, and HOMA-IR at 16 y. A total count for metabolic risk factors (MRF) was calculated using the International Diabetes Federation criteria. We used path analysis to estimate pathways and model indirect effects from BMIz-10y, controlling for child age and sex and maternal body mass index (BMI).ResultsParticipants were 54% male; mean BMIz-10y of 0.53 (SD = 1.02); mean MRF of 1.3 (SD = 0.9); mean HOMA-IR of 1.8 (SD = 1.3). Path analysis showed that BMIz-10y directly and indirectly related to increased MRF via A:L and HOMA-IR. Ghrelin was not in the metabolic pathway from BMIz-10y to MRF but was related to MRF via HOMA-IR.ConclusionThese results elucidate metabolic pathways involving child weight status, IR and metabolic risk in adolescents. Childhood BMI was an indirect risk factor for adolescent cardiometabolic risk via several pathways that involved BMI, appetite hormones, markers of inflammation, and insulin resistance during adolescence. Findings illustrate the adverse effect that childhood obesity has on adolescent health outcomes, which sets precedence for health outcomes over the life course.