Intermittent Fasting‐Induced Orm2 Promotes Adipose Browning via the GP130/IL23R‐p38 Cascade

Abstract

AbstractIntermittent fasting (IF) plays a critical role in mitigating obesity, yet the precise biological mechanisms require further elucidation. Here Orosomucoid 2 (Orm2) is identified as an IF‐induced hepatokine that stimulates adipose browning. IF induced Orm2 expression and secretion from the liver through peroxisome proliferator‐activated receptor alpha (PPARα). In adipose tissue, Orm2 bound to glycoprotein 130/interleukin 23 receptor (GP130/IL23R) and promoted adipose browning through the activation of p38 mitogen‐activated protein kinases (p38‐MAPK). In obese mice, Orm2 led to a significant induction of adipose tissue browning and subsequent weight loss, an effect that is not replicated by a mutant variant of Orm2 deficient in GP130/IL23R binding capability. Crucially, genetic association studies in humans identified an obesity‐associated Orm2 variant (D178E), which shows decreased GP130/IL23R binding and impaired browning capacity in mice. Overall, the research identifies Orm2 as a promising therapeutic target for obesity, mediating adipose browning through the GP130/IL23R‐p38 signalling pathway.