Neurosecretory protein GL induces fat accumulation in mice

Abstract

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.

Hypothalamic Overexpression of Neurosecretory Protein GL Leads to Obesity in Mice

“…We have demonstrated that NPGL is involved in energy homeostasis in vertebrates, including birds and rodents [13–16, 26, 27]. In particular, we recently showed that Npgl overexpression modestly stimulated feeding behavior and fat accumulation in rats [14].…”

“…Our previous study showed that chronic i.c.v. infusion of NPGL for 13 days reduced energy expenditure and locomotor activity in mice [16]. On the other hand, many studies have demonstrated that obesity resulting from fat accumulation is closely related to inflammation in the WAT [17, 29, 30].…”

Effects of Irregular Feeding on the Daily Fluctuations in mRNA Expression of the Neurosecretory Protein GL and Neurosecretory Protein GM Genes in the Mouse Hypothalamus

“…The feeding regulatory neuropeptides and lipid metabolic enzymes have been shown to display rhythmic activity, contributing to feeding and metabolic rhythms [20][21][22]27,28]. We had recently identified novel brain substances (NPGL and NPGM) in birds and rodents and demonstrated their important roles in regulating feeding behavior and fat accumulation [30,31,[33][34][35]. However, the relationship between the biological rhythm and NPGL/NPGM expression has not been clarified.…”

“…Recently, we discovered two novel cDNAs (viz., neurosecretory protein GL (Npgl) and its paralog neurosecretory protein GM (Npgm)) that encode the precursors of NPGL and NPGM, respectively, in chicken, rat, mouse, and human brains [29][30][31][32]. We revealed that NPGL is expressed in the mediobasal hypothalamus (MBH) of mouse and rat brains and promotes feeding and fat accumulation [30,31,33]. It is likely that NPGM has a similar biological function because both neurosecretory proteins are produced in the same neuron [32].…”

“…Additionally, the circadian expression of the representative clock genes (Bmal1, Per2, Cry1, and Nr1d1) as described above was confirmed in several tissues. The diurnal mRNA expression profiles of the crucial feeding regulatory neuropeptides and precursor protein (Npy, Orx, Mch, and Pomc) as mentioned above and lipid metabolic enzymes (typical lipogenic and lipolytic enzymes) including Fasn in central and peripheral tissues were also analyzed because NPGL might regulate feeding and promote de novo lipogenesis [30,31,[33][34][35].…”