Mechanisms underlying the central regulation of food intake and fat accumulation are not fully understood. We found that neurosecretory protein GL (NPGL), a newly-identified neuropeptide, increased food intake and white adipose tissue (WAT) in rats. NPGL-precursor gene overexpression in the hypothalamus caused increases in food intake, WAT, body mass, and circulating insulin when fed a high calorie diet. Intracerebroventricular administration of NPGL induced de novo lipogenesis in WAT, increased insulin, and it selectively induced carbohydrate intake. Neutralizing antibody administration decreased the size of lipid droplets in WAT. Npgl mRNA expression was upregulated by fasting and low insulin levels. Additionally, NPGL-producing cells were responsive to insulin. These results point to NPGL as a novel neuronal regulator that drives food intake and fat deposition through de novo lipogenesis and acts to maintain steady-state fat level in concert with insulin. Dysregulation of NPGL may be a root cause of obesity.DOI: http://dx.doi.org/10.7554/eLife.28527.001

We have recently identified from the avian hypothalamus a complementary DNA encoding a small secretory protein termed neurosecretory protein GL (NPGL). In chicks, NPGL increases body weight gain without affecting food intake. A database search reveals that NPGL is conserved throughout vertebrates. However, the central distribution and functional role of NPGL remains to be elucidated in mammals. In this study, we identified the precursor complementary DNA encoding NPGL from the mouse hypothalamus. Quantitative reverse transcription polymerase chain reaction and morphological analyses revealed that NPGL precursor messenger RNA is robustly expressed in the mediobasal hypothalamus with NPGL neurons specifically localized to the lateroposterior part of the arcuate nucleus in the hypothalamus. NPGL-immunoreactive fibers were observed in close anatomical contact with pro-opiomelanocortin neurons in the rostral region of the arcuate nucleus. NPGL messenger RNA expression was elevated by 24-hour fasting and reduced by feeding of a high-fat diet for 5 weeks. Furthermore, intracerebroventricular injection of mature NPGL increased food intake, pointing to an important role in feeding. Taken together, these findings report on the distribution of NPGL in the mammalian brain and point to an important role for this neuropeptide in energy homeostasis.

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We recently discovered a novel gene encoding a small secretory protein, neurosecretory protein GL (NPGL), which stimulates feeding behavior in mice following acute administration. These findings suggest that dysregulation of NPGL contributes to obesity and metabolic disease. To explore this possibility, we investigated the impact of prolonged exposure to NPGL through 13 days of chronic intracerebroventricular (i.c.v.) infusion and examined feeding behavior, body composition, expressions of lipid metabolic factors, respiratory metabolism, locomotor activity, and food preference. Under standard chow diet, NPGL increased white adipose tissue (WAT) mass without affecting feeding behavior and body mass. In contrast, when fed a high-calorie diet, NPGL stimulated feeding behavior and increased body mass concomitant with marked fat accumulation. Quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that mRNA expressions for key enzymes and related factors involved in lipid metabolism were increased in WAT and liver. Likewise, analyses of respiratory metabolism and locomotor activity revealed that energy expenditure and locomotor activity were significantly decreased by NPGL. In contrast, selective feeding of macronutrients did not alter food preference in response to NPGL, although total calorie intake was increased. Immunohistochemical analysis revealed that NPGL-containing cells produce galanin, a neuropeptide that stimulates food intake. Taken together, these results provide further support for NPGL as a novel regulator of fat deposition through changes in energy intake and locomotor activity.