Phillyrin restores catecholamine sensitivity in obese adipose tissue by suppressing the IL-6R-STAT3-ERK1/2 positive feedback loop

Obesity induces catecholamine resistance in adipose tissue, which impairs lipolysis and reduces energy expenditure. Here, we show that phillyrin attenuates catecholamine resistance in obese adipose tissue in association with suppression of the IL-6R–STAT3–ERK1/2 positive feedback loop. In high-fat diet (HFD)-induced obese mice, low-dose phillyrin (1 mg/kg) significantly elevated 24-h energy expenditure and oxygen consumption. It also markedly enhanced β3-adrenergic-stimulated lipolysis in both visceral and subcutaneous adipose depots, accompanied by increased phosphorylation of hormone-sensitive lipase (HSL) at Ser660. Furthermore, phillyrin effectively rescued IL-6-induced catecholamine resistance both in vitro and in vivo. Mechanistically, phillyrin downregulated IL-6Rα expression and suppressed the phosphorylation of STAT3 (Tyr705) and ERK1/2, consistent with attenuation of the self-amplifying inflammatory loop that desensitizes β-adrenergic signaling. These findings implicate the IL-6R–STAT3–ERK1/2 positive feedback loop as a mediator of obesity-associated catecholamine resistance and support phillyrin as a promising therapeutic candidate for improving lipolytic capacity and metabolic homeostasis in obesity.