Neurosecretory protein GL induces fat accumulation in mice

in Journal of Endocrinology

Correspondence should be addressed to K Ukena: ukena@hiroshima-u.ac.jp

*(K Shikano, E Iwakoshi-Ukena and T Saito contributed equally to this work)

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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.

Supplementary Materials

    • Supplementary Figure 1. Effect of chronic intracerebroventricular infusion of vehicle or neurosecretory protein GL (NPGL) (3.75 nmol/day) on food intake in animals fed standard chow (A, n=8) and a high calorie diet (B, n=6–8). Changes in food intake within 24 hr (Left), during the light period (Middle) and during the dark period (Right). Each value represents the mean ± standard error of the mean. *P<0.05, **P<0.01, ***P<0.005.
    • Supplementary Figure 2. Effect of chronic intracerebroventricular infusion of vehicle or neurosecretory protein GL (NPGL) (3.75 nmol/day) in animals fed standard chow (n=8). (A) Ratio of interscapular brown adipose tissue (BAT) mass/body mass. (B) Ratios of liver, heart, kidney, and testis mass/body mass. (C) Ratio of gastrocnemius muscle mass/body mass. Each value represents the mean ± standard error of the mean.
    • Supplementary Figure 3. Effect of chronic intracerebroventricular infusion of vehicle (V) or neurosecretory protein GL (NPGL; N) (3.75 nmol/day) on fat accumulation in animals fed a high calorie diet. (A) Representative photographs of inguinal WAT (iWAT), epididymal WAT (eWAT), retroperitoneal WAT (rWAT), and perirenal WAT (pWAT). (B) Representative photographs of interscapular BAT. (C) Representative photographs in sections of eWAT. (D) Representative photomicrographs of the sections stained by Oil Red O staining in the liver. Scale bars = 1 cm in A and B, and 100 µm in C and D.
    • Supplementary Figure 4. Effect of chronic intracerebroventricular infusion of vehicle or neurosecretory protein GL (NPGL) (3.75 nmol/day) on mRNA expression of lipid metabolism-related genes in animals fed standard chow (n=8). mRNA expression levels in inguinal WAT (iWAT) (A), retroperitoneal WAT (rWAT) (B), and liver (C). Each value represents the mean ± standard error of the mean. *P<0.05.
    • Supplementary Figure 5. Effect of chronic intracerebroventricular infusion of vehicle or neurosecretory protein GL (NPGL) (3.75 nmol/day) on respiratory metabolism. The respiratory quotient (RQ) measured in the metabolic chamber in animals fed standard chow (A, n=7–8) and animals fed a high calorie diet (B, n=5–6). Each value represents the mean ± standard error of the mean.
    • Supplementary Figure 6. Effect of chronic intracerebroventricular infusion of vehicle or neurosecretory protein GL (NPGL) (3.75 nmol/day) on food intake in animals fed macronutrient diets (n=6–7). Changes in food intake of macronutrient diets (total, protein, carbohydrate, and fat) within 24 hr (A), during the light period (B) and during the dark period (C). Each value represents the mean ± standard error of the mean. *P<0.05, **P<0.01, ***P<0.005.
    • Supplementary Figure 7. Effect of chronic intracerebroventricular infusion of vehicle (V) or neurosecretory protein GL (NPGL; N) (3.75 nmol/day) on fat accumulation in animals fed macronutrient diets. (A) Representative photographs of inguinal WAT (iWAT), epididymal WAT (eWAT), and retroperitoneal WAT (rWAT). (B) Representative photographs of the liver. Scale bars = 1 cm.
    • Supplementary Figure 8. Effect of chronic intracerebroventricular infusion of vehicle or neurosecretory protein GL (NPGL) (3.75 nmol/day) on mRNA expression in animals fed macronutrient diets (n=5–7). mRNA expression levels of lipid metabolism-related genes in epididymal WAT (eWAT) (A) and liver (B). Each value represents the mean ± standard error of the mean. *P<0.05, **P<0.01.
    • Supplementary Figure 9. Effect of chronic intracerebroventricular infusion of vehicle or neurosecretory protein GL (NPGL) (3.75 nmol/day) on mRNA expression in animals fed a high calorie diet (n=6–8). mRNA expression levels of neuropeptide genes in the hypothalamus. Each value represents the mean ± standard error of the mean. *P<0.05.

 

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