Hypothalamus is the center of energy metabolism and feeding behavior, and several hypothalamic neurotransmitters regulate energy homeostasis. Neurosecretory protein GL (NPGL) and neurosecretory protein GM (NPGM), were discovered as a novel neuropeptide from hypothalamus in 2014, induced obese phenotype owing to increased feeding behavior and lipogenesis in rats. However, the mechanisms of energy metabolism mediated by NPGL/NPGM system has not been totally elucidated. To investigate the loss of function of NPGL/NPGM system in mammals, we have established NPGL and NPGM double knockout mice (NPGL/NPGM dKO). NPGL/NPGM dKO showed a lean phenotype under a high fat diet condition because of decreased food intake and increased energy expenditure compared with wild type mice (WT). Furthermore, NPGL/NPGM dKO showed not only decreased fat deposition but also augmented thermogenic uncoupling protein 1 (UCP1) expression in brown adipose tissue. Sympathetic nervous activity in BAT were elevated in NPGL/NPGM dKO to regulate BAT thermogenesis. Finally, we analyzed expression levels of feeding regulators in hypothalamus. The expression levels of anorexigenic factors were upregulated in NPGL/NPGM dKO. These results imply that endogenous NPGL/NPGM system has important roles in central regulation of energy metabolism.