Rhein antagonizes glucocorticoid receptor signaling to activate SIRT1-dependent thermogenesis in brown adipose tissue and ameliorate obesity.

BACKGROUND

The obesity pandemic necessitates therapies that safely increase energy expenditure. Brown adipose tissue (BAT) is a key organ for energy dissipation. While the natural compound rhein has anti-obesity effects, its action on BAT and the mechanism remain unclear.

PURPOSE: This study examined the effects of rhein on BAT activation and its underlying mechanism.

STUDY DESIGN AND

METHODS

Diet-induced obese wildtype (WT) and adipocyte-specific Sirt1 knockout (AKO) mice were treated with rhein. Metabolic phenotyping including energy expenditure was measured. Brown adipocytes were differentiated in vitro and treated with rhein. Biotin-labeled rhein pull-down and glucocorticoid receptor (GR) activity assays were conducted to identify the molecular target of rhein and assess its effect on GR activity.

RESULTS

Rhein treatment robustly protected mice from high-fat diet-induced obesity, improved glucose homeostasis, and increased whole-body energy expenditure. These benefits were accompanied by BAT activation, as evidenced by elevated body temperature, upregulation of UCP1, and enhanced mitochondrial biogenesis. Mechanistically, rhein directly bound to the ARGLU1, a co-activator of GR, thereby antagonizing GR signaling. This inhibition relieved GR-mediated suppression of JNK, leading to JNK-dependent phosphorylation and stabilization of SIRT1. Critically, the anti-obesity and thermogenic effects of rhein were significantly abolished in AKO mice. Furthermore, rhein effectively counteracted corticosterone-induced obesity, BAT whitening, and SIRT1 downregulation.

CONCLUSION

Our findings identify rhein as a potent BAT activator that ameliorates obesity through a novel ARGLU1-GR-JNK-SIRT1 axis. This work not only unravels the molecular mechanism of rhein-elicited metabolic benefits in BAT, but also positions it as a promising therapeutic candidate for both overnutrition- and glucocorticoid-related metabolic disorders.