Avian GCGR-mediated continuous fat utilization offers perspectives for obesity treatment.

Human obesity is the fifth leading cause of global mortality. Fat mass loss and maintenance are central challenges for obesity management. In contrast, birds exhibit modest weight gain and limited fat accumulation due to rapid fat utilization as flight fuel. The physiology of this adaptation remained a mystery for a century. Here we show that cross-species single-nucleus RNA-sequencing analysis revealed high GCGR expression levels in avian adipocytes, while minimal in the adipose tissue of other vertebrates. Avian GCGR employs a unique rapid fat utilization mechanism for retaining a light body. Avian GCGR or other constitutively active GCGR variants (human GCGRH339R) expressed in white adipose tissue of male mice with obesity effectively promoted fat mobilization and sustained body weight loss, with decreased food intake partially contributing to the observed weight reduction. We suggest that avian GCGR plays this crucial role for fat utilization and may offer therapeutic potential for human obesity.