Roles of the FAM237-derived small proteins in energy homeostasis: a comparative perspective of neurosecretory protein GL and GM across vertebrates

Hypothalamic neuropeptides and neural circuits integrate peripheral signals, nutrient demand, and environmental cues to orchestrate energy homeostasis in vertebrates. Neurosecretory protein GL (NPGL) and neurosecretory protein GM (NPGM) are hypothalamic small secretory proteins encoded by paralogous genes of the FAM237 family. These genes were initially identified in birds, but database search showed evolutionary conservation across vertebrates, suggesting conserved physiological roles for NPGL and NPGM. Previous studies on NPGL have demonstrated that NPGL stimulates overeating and fat accumulation in a diet- and strain-dependent manner in both mammals and birds. Accumulating evidence suggests that NPGM may also be involved in hyperphagia and adiposity. Notably, recent progress in transcriptomics and histological analyses has revealed expression of Npgl and Npgm in specific hypothalamic neuronal subpopulations involved in energy homeostasis. Here, we summarize recent progress in understanding the metabolic actions of NPGL and NPGM. We then focus on the cellular identity of Npgl- and Npgm-expressing neurons. Finally, we discuss future directions and potential molecular mechanisms of metabolic regulation by NPGL and NPGM. Investigating the NPGL/NPGM system, which regulates energy metabolism, will contribute to understanding both conserved and species-specific mechanisms of energy homeostasis across vertebrates.