Effects of Omega-3 and Omega-9 Fatty Acid Supplementation on HOMA-IR and Inflammatory Markers in Children with Obesity and Insulin Resistance: A Triple-Blind RCT with Post-Intervention Follow-Up

Background/Objectives: Omega-3 and omega-9 fatty acid supplementation has shown metabolic and immunomodulatory benefits, but evidence in pediatric insulin resistance is limited, and the persistence of effects after treatment discontinuation remains uncharacterized. This study evaluated the independent and combined effects of omega-3 and omega-9 supplementation on the metabolic and inflammatory profile of children with obesity and insulin resistance, during and after active treatment. Methods: This prespecified secondary analysis of a multicenter, randomized, triple-blind, three-arm parallel trial (NCT05488223) included 97 children (8–17 years) with overweight/obesity and baseline insulin resistance (HOMA-IR > 3.0). Participants received 1.8 g/day of omega-3 (n = 32), omega-9 (n = 34), or combined supplementation (n = 31) for 3 months, followed by a 2-month post-intervention follow-up. Metabolic and inflammatory markers were assessed at baseline (T1), end of treatment (T2), and follow-up (T3). The primary outcome was the change in HOMA-IR from T1 to T2. Results: Active supplementation significantly reduced fasting insulin and HOMA-IR in the Combined (p < 0.001) and Omega-9 (p = 0.010 and p = 0.006) groups; at month 5, only the Combined group maintained significant reductions in both. IL-6 and leptin decreased across all groups during intervention and remained reduced at follow-up. Multivariable regression (n = 96) showed the metabolic response was most strongly associated with baseline metabolic status and concurrent BMI reduction rather than intervention group, which was not an independent predictor of metabolic response, nor consistently of inflammatory outcomes (one exception: a smaller IL-4 increase with omega-9, p = 0.043, unconfirmed in GEE). Conclusions: Within-group reductions in HOMA-IR and fasting insulin persisted after discontinuation only in the Combined group, but without significant between-group differences at any timepoint, consistent with response magnitude reflecting baseline status and adiposity reduction rather than treatment group per se. This positions combined supplementation as a potential metabolic adjuvant—not a standalone therapy—for HOMA-IR-defined insulin resistance in pediatric obesity, assessed here via anthropometric and biochemical rather than imaging-based measures.