Abstract
Neuropeptide Y (NPY) and agouti-related protein (AgRP) have powerful stimulatory effects on food intake, which suggests that the downregulation of brain NPY or AgRP may help reduce obesity and diabetes by inhibiting food intake. To search for active compounds that inhibit NPY and AgRP expression, we made two luciferase reporter assay systems consisting of NPY and AgRP promoter-driven luciferase genes, together with the puromycin resistance gene, in a plasmid vector. Each plasmid was permanently transfected into N29-4 neuronal cells. Using the systems, resveratrol was purified from the stem of Vitis coignetiae Pulliat by activityguided fractionation. Resveratrol downregulated NPY and AgRP promoter-driven luciferase activity in a dose-dependent manner. The inhibitory concentrations (IC50, 50% inhibition) of resveratrol against pNPY-luc and pAgRP-luc activities were 8.9 μM and 8.0 μM, respectively. Furthermore, one-time intraperitoneal injection of resveratrol (100 mg/kg) suppressed 20.0% and 17.2% of food intake during 24 and 48 h, respectively. These results indicated that resveratrol inhibited food intake, which may be related to the downregulation of NPY and AgRP gene expression.
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Argyropoulos, G., Rankinen, T., Neufeld, D. R., Rice, T., Province, M. A., and Leon, A. S., A polymorphism in the human agouti-related protein is associated with late-onset obesity. J. Clin. Endocrinol. Metab., 87, 4198–4202 (2002).
Athar, M., Back, J. H., Kopelovich, L., Bickers, D. R., and Kim, A. L., Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms. Arch. Biochem. Biophys., 486, 95–102 (2009).
Aziz, M. H., Kumar, R., and Ahmad, N., Cancer chemoprevention by resveratrol: In vitro and in vivo studies and the underlying mechanisms (review). Int. J. Oncol., 23, 17–28 (2003).
Baolin, L., Inami, Y., Tanaka, H., Inagaki, N., Iinuma, M., and Nagai, H., Resveratrol inhibits the release of mediators from bone marrow-derived mouse mast cells in vitro. Planta Med., 70, 305–309 (2004).
Bertelli, A. A., Wine, research and cardiovascular disease: instructions for use. Atherosclerosis, 195, 242–247 (2007).
Chen, W. P., Chi, T. C., Chuang, L. M., and Su, M. J., Resveratrol enhances insulin secretion by blocking K (ATP) and K(V) channels of beta cells. Eur. J. Pharmacol., 568, 269–277 (2007).
De-Rijke, C. E., Hillebrand, J. J., Verhagen, L. A., Roeling, T. A., and Adan, R. A., Hypothalamic neuropeptide expression following chronic food restriction in sedentary and wheel-running rats. J. Mol. Endocrinol., 35, 381–390 (2005).
Ding, B., Kull, B., Liu, Z., Mottagui-Tabar, S., Thonberg, H., Gu, H. F., Brookes, A. J., Grundemar, L., Karlsson, C., Hamsten, A., Arner, P., Ostenson, C. G., Efendic, S., Monné, M., von Heijne, G., Eriksson, P., and Wahlestedt, C., Human neuropeptide Y signal peptide gain-of-function polymorphism is associated with increased body mass index: possible mode of function. Regul. Pept., 127, 45–53 (2005).
Do, G. M., Kwon, E. Y., Kim, H. J., Jeon, S. M., Ha, T. Y., Park, T., and Choi, M. S., Long-term effects of resveratrol supplementation on suppression of atherogenic lesion formation and cholesterol synthesis in apo E-deficient mice. Biochem. Biophys. Res. Commun., 374, 55–59 (2008).
Fan, E., Zhang, L., Jiang, S., and Bai, Y., Beneficial effects of resveratrol on atherosclerosis. J. Med. Food, 11, 610–614 (2008).
Fremont, L., Biological effects of resveratrol. Life Sci., 66, 663–673 (2000).
Harrold, J. A., Williams, G., and Widdowson, P. S., Changes in hypothalamic agouti-related protein (AGRP), but not alpha-MSH or pro-opiomelanocortin concentrations in dietary-obese and food-restricted rats. Biochem. Biophys. Res. Commun., 258, 574–577 (1999).
Haskell-Luevano, C. and Monck, E. K., Agouti-related protein functions as an inverse agonist at a constitutively active brain melanocortin-4 receptor. Regul. Pept., 99 1–7 (2001).
Kalra, S. P., Dube, M. G., Sahu, A., Phelps, C. P., and Kalra, P. S., Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc. Natl. Acad. Sci. U S A, 88, 10931–10935 (1991).
Katsuki, A., Sumida, Y., Gabazza, E. C., Murashima, S., Tanaka, T., Furuta, M., Araki-Sasaki, R., Hori, Y., Nakatani, K., Yano, Y., and Adachi, Y., Plasma levels of agouti-related protein are increased in obese men. J. Clin. Endocrinol. Metab., 86, 1921–1924 (2001).
Mashiko, S., Moriya, R., Ishihara, A., Gomori, A., Matsushita, H., Egashira, S., Iwaasa, H., Takahashi, T., Haga, Y., Fukami, T., and Kanatani, A., Synergistic interaction between neuropeptide Y1 and Y5 receptor pathways in regulation of energy homeostasis. Eur. J. Pharmacol., 615, 113–117 (2009).
McNulty, J. C., Jackson, P. J., Thompson, D. A., Chai, B., Gantz, I., Barsh, G. S., Dawson, P. E., and Millhauser, G. L., Structures of the agouti signaling protein. J. Mol. Biol., 346, 1059–1070 (2005).
Moon, H. K., Yang, E. S., and Park, J. W., Protection of peroxynitrite-induced DNA damage by dietary antioxidants. Arch. Pharm. Res., 29, 213–217 (2006).
Muraoka, O., Xu, B., Tsurumaki, T., Akira, S., Yamaguchi, T., and Higuchi, H., Leptin-induced transactivation of NPY gene promoter mediated by JAK1, JAK2 and STAT3 in the neural cell lines. Neurochem. Int., 42, 591–601 (2003).
Ollmann, M. M., Wilson, B. D., Yang, Y. K., Kerns, J. A., Chen, Y., Gantz, I., and Barsh G. S., Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related-protein. Science, 278, 135–138 (1997).
Patel, H. R., Qi, Y., Hawkins, E. J., Hileman, S. M., Elmquist, J. K., Imai, Y., and Ahima, R. S., Neuropeptide Y deficiency attenuates responses to fasting and high-fat diet in obesity-prone mice. Diabetes, 55, 3091–3098 (2006).
Pritchard, L. E. and White, A., Agouti-related protein: more than a melanocortin-4 receptor antagonist? Peptides, 26, 1759–1770 (2005).
Sharma, S., Anjaneyulu, M., Kulkarni, S. K., and Chopra, K., Resveratrol, a polyphenolic phytoalexin, attenuates diabetic nephropathy in rats. Pharmacology, 76, 69–75 (2006).
Sweet, D. C., Levine, A. S., and Kotz, C. M., Functional opioid pathways are necessary for hypocretin-1 (orexin-A)-induced feeding. Peptides, 25, 307–314 (2004).
Valassi, E., Scacchi, M., and Cavagnini, F., Neuroendocrine control of food intake. Nutr. Metab. Cardiovasc. Dis., 18, 158–168 (2008).
Yang, L., Scott, K. A., Hyun, J., Tamashiro, K. L., Tray, N., Moran, T. H., and Bi, S., Role of dorsomedial hypothalamic neuropeptide Y in modulating food intake and energy balance. J. Neurosci., 29, 179–190 (2009).
Yuan, L., Ni, Y., Barth, S., Wang, Y., Grossmann, R., and Zhao, R., Layer and broiler chicks exhibit similar hypothalamic expression of orexigenic neuropeptides but distinct expression of genes related to energy homeostasis and obesity. Brain Res., 1273, 18–28 (2009).
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Kim, SJ., Lee, Y.H., Han, MD. et al. Resveratrol, purified from the stem of Vitis coignetiae Pulliat, inhibits food intake in C57BL/6J Mice. Arch. Pharm. Res. 33, 775–780 (2010). https://doi.org/10.1007/s12272-010-0518-5
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DOI: https://doi.org/10.1007/s12272-010-0518-5