Multi-Axis Functional Mechanisms of the Milpa Diet in Obesity: A Scoping Review

Background: Obesity is a multifactorial metabolic disorder characterized by chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, dysregulated adipogenesis, and alterations in the gut microbiota, which collectively contribute to insulin resistance and cardiometabolic complications. In this context, dietary patterns rich in bioactive compounds have gained relevance as potential strategies to modulate these interconnected pathways. Objective: To assess the potential of the Milpa Diet (a sustainable, plant-dominant Mesoamerican eating pattern centered on the ancient three sisters’ polyculture of maize, beans, and squash, along with chili) as a culturally relevant, multi-axis functional dietary pattern, and to evaluate the molecular mechanisms underlying obesity-associated with metabolic dysfunction. Methods: A scoping review of preclinical and clinical studies was conducted using Medline via PubMed, Scopus, and Web of Science databases. The ChEMBL database was also used to identify chemical structures. The search focused on evidence related to inflammation, oxidative stress, adipogenesis, lipotoxicity, mitochondrial function, and gut microbiota modulation in the context of the main foods of the Milpa Diet, including maize, legumes, chili peppers, nopal, and quelites. Studies were selected based on peer-review status and their relevance to molecular, metabolic, and functional outcomes. Results: The current evidence shows that the core components of the Milpa Diet provide dietary fiber and a broad range of bioactive compounds, such as flavonoids, carotenoids, capsaicinoids, phenolic acids, pigments, and vitamins, which exhibit antioxidant and anti-inflammatory effects. These compounds have been associated with modulation of adipogenesis and lipotoxicity, preservation of mitochondrial function, and favorable regulation of gut microbiota composition and activity, collectively influencing metabolic pathways relevant to obesity. Conclusions: Overall, mechanistic and emerging clinical evidence suggests that the Milpa Diet represents a multi-axis nutritional strategy with potential to mitigate obesity-related metabolic dysfunction through coordinated effects on inflammation, oxidative stress, adipogenesis, lipotoxicity, mitochondrial function, and gut microbiota regulation. Although comprehensive clinical trials evaluating this dietary pattern as an integrated intervention remain limited, current evidence supports its relevance for future translational research, public health strategies, and the development of sustainable dietary models aimed at improving metabolic health.