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.

We recently found a previously unidentified cDNA in chicken hypothalamus which encodes the precursor for neurosecretory protein GL (NPGL). A previous study showed that intracerebroventricular (i.c.v.) infusion of NPGL caused body mass gain in chicks. However, it was not clear which part(s) of the body gained mass. In the present study, we investigated which tissues increased in mass after chronic i.c.v. infusion of NPGL in chicks. We found that NPGL increased the masses of the liver, abdominal fat, and subcutaneous fat, while NPGL did not affect the masses of muscles, including pectoralis major, pectoralis minor, and biceps femoris. Oil Red O staining revealed that fat deposition had occurred in the liver. In addition, the size of the lipid droplets in the abdominal fat increased. Furthermore, we found an upregulation of lipogenesis and downregulation of lipolysis in the abdominal fat, but not in the liver. These results indicate that NPGL is involved in fat storage in chicks.

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Recently, we discovered a novel cDNA encoding the precursor of a small secretory protein, neurosecretory protein GL (NPGL), in the hypothalamic infundibulum of chickens. NPGL plays an important role in the regulation of growth and feeding. A database search indicated that the NPGL gene has a paralogous gene: neurosecretory protein GM (NPGM), also in chickens. We identified cDNA encoding the NPGM precursor in chickens. Morphological analysis showed that NPGM-containing cells are specifically localized in the medial mammillary nucleus (MM) and infundibular nucleus (IN) in the hypothalamus. In addition, we found that NPGM and NPGL are co-localized, especially in the MM. The expression levels of NPGM mRNA gradually decreased during post-hatch development, in contrast to those of NPGL mRNA. Moreover, we investigated the relationship between NPGM and other known factors. NPGM was found to be produced in histaminergic neurons in the MM. NPGM and histidine decarboxylase, a histamine-producing enzyme, displayed similar expression patterns during post-hatch development. Acute intracerebroventricular injection of NPGM decreased food intake, similar to the effect of histamine. To our knowledge, this is the first report of the localization and function of NPGM in the brain of vertebrates. These results will further advance the understanding mechanisms underlying energy homeostasis.

<b><i>Introduction:</i></b> The mechanisms underlying obesity are not fully understood, necessitating the creation of novel animal models for the investigation of metabolic disorders. We have previously found that neurosecretory protein GL (NPGL), a newly identified hypothalamic neuropeptide, is involved in feeding behavior and fat accumulation in rats. However, the impact of NPGL on obesity remains unclear in any animal model. The present investigation sought to elucidate whether NPGL causes obesity in the obesity-prone mouse strain C57BL/6J. <b><i>Methods:</i></b> We overexpressed the NPGL-precursor gene (<i>Npgl</i>) in the hypothalamus using adeno-associated virus in male C57BL/6J mice fed normal chow (NC) or a high-calorie diet (HCD). After 9 weeks of <i>Npgl</i> overexpression, we measured adipose tissues, muscle, and several organ masses in addition to food intake and body mass. To assess the effects of <i>Npgl</i> overexpression on peripheral tissues, we analyzed mRNA expression of lipid metabolism-related genes by quantitative RT-PCR. Whole body energy consumption was assessed using an O₂/CO₂ metabolism measurement before an apparent increase in body mass. <b><i>Results:</i></b> <i>Npgl</i> overexpression increased food intake, body mass, adipose tissues and liver masses, and food efficiency under both NC and HCD, resulting in obesity observable within 8 weeks. Furthermore, we observed fat accumulation in adipose tissues and liver. Additionally, mRNA expression of lipid metabolism-related factors was increased in white adipose tissue and the liver after <i>Npgl</i> overexpression. <i>Npgl</i> overexpression inhibited energy expenditure during a dark period. <b><i>Conclusion:</i></b> Taken together, the present study suggests that NPGL can act as an obesogenic factor that acts within a short period of time in mice. As a result, this <i>Npgl</i> overexpression-induced obesity can be widely applied to study the etiology of obesity from genes to behavior.