Rsk4 Mediates Brain FGF19 Signaling to Constrain Diet-Induced Obesity in Mice

Central administration of fibroblast growth factor-19 (FGF19) has been shown to reduce body weight in obese mice, but the underlying mechanisms remain largely unknown. Here, we show that ribosomal S6 kinase 4 (Rsk4) is required for FGF19 to counteract obesity. Rsk4 is predominantly expressed in hypothalamic neurons. While loss of Rsk4 has negligible effects on energy homeostasis under basal conditions, it exacerbates diet-induced obesity (DIO) in mice due to hyperphagia. These mice also exhibit glucose intolerance and insulin resistance. Reexpression of Rsk4 in mediobasal hypothalamic neurons largely reverses the metabolic abnormalities caused by Rsk4 deletion. We further show that central FGF19 administration suppresses food intake and reduces body weight in control mice, whereas these effects are markedly blunted in Rsk4 knockout mice. Collectively, these findings reveal that hypothalamic neuronal Rsk4 constrains DIO in mice, likely through its critical role in central FGF19 signaling. Article Highlights Ribosomal S6 kinase 4 (Rsk4) is predominantly expressed in hypothalamic neurons. Rsk4 is negligible for maintaining energy homeostasis in mice. Loss of Rsk4 promotes diet-induced obesity and related metabolic disorders in mice. Rsk4 is required for central fibroblast growth factor-19 to reduce body weight in obese mice.