DHA-enriched omega-3 supplementation remodels adipose endocrine function and potentiates brown adipose secretome-mediated killing of melanoma cells

Background: Omega-3 polyunsaturated fatty acids (PUFAs) are widely recognized for their anti-inflammatory properties; however, their impact on adipose tissue metabolic programming and endocrine output remains incompletely understood. In particular, whether DHA-enriched omega-3 supplementation can reprogram adipose tissue secretory function and influence downstream cellular responses is still debated. Methods: Female C57BL/6 mice received a DHA-enriched omega-3 dietary intervention (DHA:EPA ratio 5:1) for five weeks. Systemic inflammation and oxidative stress were assessed by serum cytokine profiling and flow cytometric analysis of peritoneal lavage cells. Adipose tissue mass and morphology were evaluated across distinct depots. To investigate adipose tissue endocrine function, brown and subcutaneous white adipose tissues were cultured ex vivo, and their conditioned media were used to stimulate murine melanoma cells in vitro. Results: DHA-enriched omega-3 supplementation significantly attenuated systemic inflammatory markers and reduced oxidative stress without affecting body weight. The intervention selectively decreased white adipose tissue mass and adipocyte hypertrophy, indicating depot-specific adipose remodeling. Importantly, DHA supplementation reprogrammed adipose tissue endocrine function, resulting in qualitative changes in adipose-derived secretomes. Conditioned media from brown adipose tissue of supplemented animals displayed enhanced cytotoxic activity against melanoma cells, accompanied by reduced melanoma-derived interleukin-6 production, indicating modulation of tumor-associated inflammatory signaling. Conclusions: These findings demonstrate that DHA-enriched omega-3 supplementation remodels adipose tissue metabolism and endocrine function, leading to a brown adipose tissue secretome with enhanced cytotoxic and anti-inflammatory effects on melanoma cells. Adipose tissue endocrine reprogramming emerges as a nutritionally driven mechanism with potential relevance for metabolic regulation and cancer-associated inflammatory crosstalk.