Phytochemicals and Irisin as Multi-Target Regulators of Adipose Tissue Browning and Metabolic Reprogramming: Synergies with GLP-1 Pathways

Background: Obesity is a multifaceted metabolic disorder characterized by systemic disturbances, particularly impaired energy homeostasis, chronic low-grade inflammation, and mitochondrial dysfunction across the brain, gut, adipose tissue, and liver axes. Objectives: This review aims to examine the metabolic properties and molecular mechanisms of six key phytochemicals (berberine, resveratrol, catechins, capsaicin, thymoquinone, and phycocyanin) and the exercise-induced myokine irisin, and their roles in mitochondrial signaling and metabolic reprogramming. Sources of Evidence: A comprehensive literature search was conducted across major electronic databases, including PubMed, Web of Science, and Scopus, to identify relevant mechanistic, in vivo, and in vitro studies. Results: Both the selected phytochemicals and irisin act as multi-target regulators that modulate key signaling pathways, including AMPK, PI3K/Akt/mTOR, SIRT1, Nrf2, and PPARγ. These phytochemicals and irisin can drive cell- and tissue-specific metabolic reprogramming, promoting the browning of white adipocytes, suppressing de novo lipogenesis in hepatocytes, and enhancing fatty acid oxidation in skeletal myocytes. This synergistic metabolic reprogramming enhances thermogenesis and increases energy expenditure. Conclusions: Co-targeting redox signaling and metabolic pathways via phytochemicals and irisin offers a powerful strategy against obesity. This integrative framework restores multi-organ homeostasis, laying the groundwork for targeted metabolic therapies.