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

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.

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

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.

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.

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.