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Background: Protein intake among children in resource-rich countries often exceeds current recommendations. Higher protein consumption during infancy has been associated with an increased risk of obesity later in life.

Objectives: We conducted a secondary analysis of a randomized controlled trial where 250 infants were randomly assigned to receive either a protein-reduced Nordic diet or a conventional Swedish complementary diet. Our aims were to examine the metabolic responses to the intervention using plasma metabolomics and to test the pathways proposed by the Early Protein Hypothesis by linking cumulative protein intake to circulating branched-chain amino acids (BCAAs), insulin-like growth factor-1 (IGF-1), and growth outcomes using structural equation modeling (SEM).

Methods: Targeted proton nuclear magnetic resonance (1H-NMR) metabolomics was performed on plasma samples collected at 12 and 18 mo. Two SEM models were constructed: one modeled body weight and the other modeled BMI as growth outcomes using data collected up to age 18 mo. Model fit indices were assessed, and path diagrams were used to visualize relationships.

Results: The Nordic diet led to reduced-protein intake and a distinct infant plasma metabolomic profile. Circulating BCAAs and their catabolites were significantly lower in the reduced-protein Nordic diet compared with the conventional diet. Cumulative protein intake positively correlated with plasma IGF-1 concentrations {weight-based SEM: β = 0.40 [95% confidence interval (CI): 0.03, 0.48]; BMI-based SEM: β = 0.43 [95% CI: 0.05, 0.50]}. Plasma total BCAAs were positively associated with plasma IGF-1 levels [weight-based SEM: β = 0.16 (95% CI: 0.00, 0.76); BMI-based SEM: β = 0.17 (95% CI: 0.02, 0.78)]. After accounting for metabolite-mediated effects on IGF-1 and insulin, cumulative protein intake remained significantly associated with infant body weight [β=0.36 (95% CI: 0.02, 0.99)], but not BMI.

Conclusions: Complementary feeding during infancy substantially shapes the plasma metabolome. Reducing protein intake from complementary feeding helps attenuate rapid infant weight gain, a well-established early-life predictor of later obesity.