Deletion of neurosecretory proteins GL and GM drives dual anti-obesity effects via appetite suppression and enhanced energy expenditure.

Obesity results from an imbalance between energy intake and expenditure and is regulated by hypothalamic neuropeptide systems. The neurosecretory proteins GL (NPGL) and GM (NPGM) are expressed in the hypothalamus and promote feeding in gain-of-function studies; however, their endogenous physiological roles remain unclear. Here, we show that mice lacking both NPGL and NPGM display a lean phenotype driven by reduced food intake and increased energy expenditure. This anti-obesity phenotype is associated with increased expression of anorexigenic pro-opiomelanocortin in the hypothalamus and enhanced thermogenic activity in brown adipose tissue, marked by elevated uncoupling protein 1. Consistent with these findings, suppression of NPGL/NPGM signaling reduces feeding and alters sympathetic nerve activity. In addition, genome-wide association analysis identifies an obesity-associated variant near the human NPGM locus, suggesting relevance to human energy balance. Together, these findings identify NPGL and NPGM as endogenous regulators of energy homeostasis with potential relevance to obesity.