Otopetrin 1 protects against adipose tissue wasting during cancer cachexia progression.

Cancer cachexia is a systemic metabolic disorder, with body weight loss and adipose tissue wasting as key features, and adipose tissue remodeling often preceding weight loss. Using pre-cachexia and cachexia models in Lewis lung carcinoma (LLC) tumor-bearing mice, transcriptomic analysis of white adipose tissue (WAT) identified Otopetrin 1 (Otop1) as a dynamically regulated gene, increased in pre-cachexia and decreased in cachexia. In patients with cancer, OTOP1 expression in subcutaneous WAT was reduced in cachexia and positively correlated with BMI in cachectic patients. In adipocytes treated with tumor-conditioned medium, OTOP1 overexpression alleviated metabolic dysfunction, accompanied by suppression of NF-κB signaling and activation of PPARγ, leading to reduced lipolysis and enhanced adipogenesis; these effects were partially attenuated by the PPARγ antagonist. Moreover, overexpression of OTOP1 in adipose tissue of LLC tumor-bearing mice alleviated adipose tissue wasting and improved lipid metabolism. These findings suggest a role for OTOP1 in adipose tissue remodeling during cancer cachexia.