RSK2 facilitates beige fat formation through thermogenic and glycolytic pathways.

Beige adipose tissue offers therapeutic potential for metabolic disorders. Notably, glycolytic beige adipocytes, which can be activated independently of β-adrenergic signaling, may provide unique advantages. This study aimed to investigate the role of p90 ribosomal S6 kinase-2 (RSK2) in both cold-induced and cold-independent glycolytic beige adipocyte formation. We employed C57BL/6J mice subjected to cold exposure (4 °C) or high-fat diet (HFD) and analyzed adipose tissue for thermogenic and glycolytic markers. In vitro, subcutaneous adipose-derived stem cells (primary preadipocytes) were cultured at 28 °C to mimic cold exposure. RSK2 expression was manipulated via knockdown or overexpression to evaluate its functional role. Cold exposure upregulated uncoupling protein-1 (UCP1) and RSK2 in vivo, while HFD suppressed RSK2, UCP1, enolase 1 (ENO1), and pyruvate kinase isoform M2 (PKM2). In primary preadipocytes, cold exposure induced UCP1 and RSK2 expression and reduced triglyceride accumulation. RSK2 knockdown suppressed UCP1, acetyl-CoA carboxylase (ACC), and hormone-sensitive lipase (HSL) but increased carnitine palmitoyl transferase expression. It also reduced PKM2, ENO1, and lactate production under normothermic conditions, whereas RSK2 overexpression had opposite effects. High-glucose and high-insulin treatment decreased RSK2, glycolytic and thermogenic markers, and insulin signaling, which were reversed by RSK2 overexpression. RSK2 plays a dual role in mediating cold-induced and cold-independent glycolytic beige adipocyte formation. It may serve as a promising target for treating obesity and related metabolic disorders.