EGCG combats obesity by triggering a BAT-independent thermogenic switch and remodeling the immune microenvironment in subcutaneous adipose tissue.

BACKGROUND: Dysfunctional adipose tissue drives metabolic and immune dysregulation in obesity. Adaptive thermogenesis is a promising therapy, but its efficacy is limited by low brown adipose tissue (BAT) activity. Epigallocatechin gallate (EGCG) has anti-obesity effects, yet it remains unknown whether it can trigger BAT-independent thermogenesis and remodel the adipose immunometabolic environment. OBJECTIVE: This study investigated whether EGCG counteracts diet-induced obesity by remodeling the immunometabolic microenvironment and activating BAT-independent thermogenesis. METHODS: In this study, high-fat diet-induced obese C57BL/6 J mice received EGCG intervention via gavage (5 groups, n = 8-12 per group, intervention 8 weeks) and dietary administration (4 groups, n = 8 per group, intervention 12 weeks), along with cell experiments. We evaluated the effects of EGCG on metabolic parameters, energy expenditure, adipose browning, macrophage infiltration, oxidative stress, and mitochondrial biogenesis. In addition, correlation analysis, protein-protein interaction network analysis, and molecular docking were performed to identify key targets. RESULTS: This study demonstrates that EGCG counteracts diet-induced obesity through a dual mechanism. Firstly, EGCG alleviates adipose tissue inflammation by inhibiting macrophage infiltration and reduces oxidative stress and apoptosis, thereby remodeling the immune microenvironment. More critically, EGCG unlocks a BAT-independent thermogenic pathway. EGCG was found to increase systemic energy expenditure independently of BAT function, and beige adipogenesis in subcutaneous white adipose tissue (scWAT) was also induced in an in vivo model of BAT blockade. Meanwhile, in vitro studies further confirm that EGCG directly stimulates the thermogenic capacity of adipocytes derived from scWAT progenitor cells. CONCLUSION: This study demonstrates that EGCG ameliorates adipose tissue inflammation and activates a potent BAT-independent thermogenic program in scWAT. This BAT-independent mechanism highlights the multi-target potential of EGCG against metabolic dysfunction.