Therapeutic Potential of Oleuropein and Hydroxytyrosol against Obesity Comorbidities: A Systematic Review

Obesity and its comorbidities are closely linked to chronic low-grade inflammation and oxidative stress. In this context, oleuropein (OLE) and hydroxytyrosol (HT), key bioactive compounds of the Mediterranean Diet derived from Olea europaea, emerge as potent regulatory agents at the molecular, tissue, and systemic levels. The aim of this work is to gather in vivo and clinical evidence on the antioxidant and anti-inflammatory effects of OLE and HT in the context of obesity. Following the PRISMA methodology, a systematic search was conducted across databases (PubMed, Scopus, and WoS), applying inclusion criteria such as in vivo and clinical studies, and exclusion criteria, such as other reviews, studies focused on infectious diseases, and in vitro research, resulting in 39 selected articles. Research in animal models and clinical studies demonstrates that the administration of OLE and HT attenuates body weight gain, fat accumulation in adipose tissue, and the presence of visceral adiposity. Both phenolic compounds restore glucose and lipid homeostasis by reducing fasting glucose, triglycerides, and LDL cholesterol, as well as restoring insulin sensitivity and the HOMA-IR index. At the cellular level, they exert a profound anti-inflammatory effect by inhibiting NF-κB signaling and decreasing the expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and the chemokine MCP-1. Simultaneously, they suppress oxidative stress by activating the Nrf2 transcription factor, restoring endogenous antioxidant enzymes (SOD, CAT, GPx), and consequently reducing biomarkers of oxidative damage, such as malondialdehyde (MDA). In target organs, these polyphenols protect endothelial function, decrease the hepatic steatosis score (NAS), exhibit neuroprotective effects, reduce kidney damage, restore adipose endocrine function, strengthen the intestinal barrier by increasing tight junction proteins, and restore pancreatic function. Despite their remarkable therapeutic potential, the low oral bioavailability of OLE and HT (∼5%), conditioned by a rapid phase II metabolism, raises the need to develop innovative formulations, dietary synergy strategies or food enrichment to maximize their clinical efficacy.