Abstract
Objective:
To investigate the mechanisms underlying the satiety-promoting effects of a novel protease inhibitor concentrate derived from potato (PPIC).
Methods:
The acute and prolonged effects of oral PPIC administration (100 mg kg−1 per day) on food intake, body weight and gastric emptying were evaluated in healthy rats. Parameters of body weight, food intake, plasma glucose, insulin and cholecystokinin (CCK) were measured. Duodenal proteolytic activity and CCK expression were determined in tissue extracts. Intestinal STC-1 cell culture model was used to investigate the direct effect of PPIC on CCK transcript level and secretion.
Results:
Acute oral administration of PPIC reduced immediate food intake during the first 2 h following the treatment, delayed gastric emptying and decreased proteolytic activity in the duodenum. Repeated oral ingestion of PPIC reduced weight gain in male rats and significantly elevated the plasma CCK levels. Although duodenal mucosal CCK mRNA levels increased in response to PPIC administration, the concentrate failed to elevate CCK expression or release in STC-1 cells. The 14-day ascending dose range study (33–266 mg kg−1 PPIC per day) showed no adverse side effects associated with PPIC administration.
Conclusion:
These findings provided evidence that PPIC is effective in reducing food intake and body weight gain in healthy rats when administered orally by increasing circulating CCK levels through a trypsin-dependent mechanism.
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References
Imming P, Sinning C, Meyer A . Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov 2006; 5: 821–834.
Padwal R, Kezouh A, Levine M, Etminan M . Long-term persistence with orlistat and sibutramine in a population-based cohort. Int J Obes (Lond) 2007; 31: 1567–1570.
Liener IE . The nutritional significance of plant protease inhibitors. Proc Nutr Soc 1979; 38: 109–113.
Shewry PR . Tuber storage proteins. Ann Bot 2003; 91: 755–769.
Schnebeli HP, Braun NJ . Proteinase inhibitors as drugs. In: Barrett AJ, Salvesen G (eds). Proteinase Inhibitors. Elsevier: Amsterdam, 1986, pp 613–627.
Hill AJ, Peikin SR, Ryan CA, Blundell JE . Oral administration of proteinase inhibitor II from potatoes reduces energy intake in man. Physiol Behav 1990; 48: 241–246.
Schwartz JG, Guan D, Green GM, Phillips WT . Treatment with an oral proteinase inhibitor slows gastric emptying and acutely reduces glucose and insulin levels after a liquid meal in type II diabetic patients. Diabetes Care 1994; 17: 255–262.
Levitt J . The isolation and preliminary fractionation of proteins from dormant and growing potato tubers. Plant Physiol 1951; 26: 59–65.
Bryant J, Green TR, Gurusaddaiah T, Ryan CA . Proteinase inhibitor II from potatoes: isolation and characterization of its protomer components. Biochemistry 1976; 15: 3418–3424.
Kim MH, Park SC, Kim JY, Lee SY, Lim HT, Cheong H et al. Purification and characterization of a heat-stable inhibitor from the tubers of new potato variety ‘Golden Valley”. Biochem Biophys Res Commun 2006; 346: 681–686.
Pouvreau L, Gruppen H, Piersma SR, van den Broek LA, van Koningsveld GA, Voragen AG . Relative abundance and inhibitory distribution of protease inhibitors in potato juice from cv. Elkana. J Agric Food Chem 2001; 49: 2864–2874.
Van Kaningsveld GA . Physico-chemical and functional properties of potato proteins. PhD thesis, University of Wageningen 2001.
Liddle RA, Goldfine ID, Williams JA . Bioassay of plasma cholecystokinin in rats: effects of food, trypsin inhibitor, and alcohol. Gastroenterology 1984; 87: 542–549.
Louie DS, May D, Miller P, Owyang C . Cholecystokinin mediates feedback regulation of pancreatic enzyme secretion in rats. Am J Physiol 1986; 250: G252–G259.
Fried M, Erlacher U, Schwizer W, Lochner C, Koerfer J, Beglinger C et al. Role of cholecystokinin in the regulation of gastric emptying and pancreatic enzyme secretion in humans. Studies with the cholecystokinin-receptor antagonist loxiglumide. Gastroenterology 1991; 101: 503–511.
Schafmayer A, Becker HD, Werner M, Folsch UR, Creutzfeldt W . Plasma cholecystokinin levels in patients with chronic pancreatitis. Digestion 1985; 32: 136–139.
Schneeman BO, Lyman RL . Distribution of cholecystokinin activity in the rat small intestine. Digestion 1977; 15: 28–33.
Miyasaka K, Guan DF, Liddle RA, Green GM . Feedback regulation by trypsin: evidence for intraluminal CCK-releasing peptide. Am J Physiol 1989; 257: G175–G181.
Spannagel AW, Green GM, Guan D, Liddle RA, Faull K, Reeve Jr JR . Purification and characterization of a luminal cholecystokinin-releasing factor from rat intestinal secretion. Proc Natl Acad Sci USA 1996; 93: 4415–4420.
Chavan JK, Hejgaard J . Detection and partial characterisation of subtilisin inhibitors in legume seeds by isoelectric focusing. J Sci Food Agric 1981; 32: 857–862.
Yakoby N, Raskin I . A simple method to determine trypsin and chymotrypsin inhibitory activity. J Biochem Biophys Methods 2004; 59: 241–251.
Rolls BJ, Hetherington M, Burley VJ . The specificity of satiety: the influence of foods of different macronutrient content on the development of satiety. Physiol Behav 1988; 43: 145–153.
Shi G, Leray V, Scarpignato C, Bentouimou N, Bruley des Varannes S, Cherbut C et al. Specific adaptation of gastric emptying to diets with differing protein content in the rat: is endogenous cholecystokinin implicated? Gut 1997; 41: 612–618.
Rindi G, Grant SG, Yiangou Y, Ghatei MA, Bloom SR, Bautch VL et al. Development of neuroendocrine tumors in the gastrointestinal tract of transgenic mice. Heterogeneity of hormone expression. Am J Pathol 1990; 136: 1349–1363.
Mosmann T . Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55–63.
Komarnytsky S, Borisjuk N, Yakoby N, Garvey A, Raskin I . Cosecretion of protease inhibitor stabilizes antibodies produced by plant roots. Plant Physiol 2006; 141: 1185–1193.
Kizelsztein P, Govorko D, Komarnytsky S, Evans A, Wang Z, Cefalu WT et al. 20-Hydroxyecdysone decreases weight and hyperglycemia in a diet-induced obesity mice model. Am J Physiol Endocrinol Metab 2009; 296: E433–E439.
Winer J, Jung CK, Shackel I, Williams PM . Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. Anal Biochem 1999; 270: 41–49.
Ausich R, Sheabar FZ, Stomp R, Ryan CA, Davidson B . Method for the elimination of Kunitz and Bowman-Birk trypsin inhibitors and carboxypeptidase inhibitor from potato proteins. US patent no 6686456 2004; 1–12.
Cleveland TE, Thornburg RW, Ryan CA . Molecular characterization of a wound-inducible inhibitor I gene from potato and the processing of its mRNA and protein. Plant Mol Biol 1987; 8: 199–207.
Birk Y . Plant Protease Inhibitors. Springer-Verlag New York, 2003.
Pouvreau L, Gruppen H, van Koningsveld GA, van den Broek LAM, Voragen AGJ . The most abundant protease inhibitor in potato tuber (Cv. Elkana) is a serine protease inhibitor from the Kunitz family. Journal of Agricultural and Food Chemistry 2003; 51: 5001–5005.
Cohn C, Joseph D . Changes in body composition attendant on force feeding. Am J Physiol 1959; 196: 965–968.
Cunningham KM, Daly J, Horowitz M, Read NW . Gastrointestinal adaptation to diets of differing fat composition in human volunteers. Gut 1991; 32: 483–486.
Liddle RA, Carter JD, McDonald AR . Dietary regulation of rat intestinal cholecystokinin gene expression. J Clin Invest 1988; 81: 2015–2019.
Cordier-Bussat M, Bernard C, Haouche S, Roche C, Abello J, Chayvialle JA et al. Peptones stimulate cholecystokinin secretion and gene transcription in the intestinal cell line STC-1. Endocrinology 1997; 138: 1137–1144.
Westerterp-Plantenga MS, Nieuwenhuizen A, Tome D, Soenen S, Westerterp KR . Dietary protein, weight loss, and weight maintenance. Annu Rev Nutr 2009; 29: 21–41.
Park MI, Camilleri M . Gastric motor and sensory functions in obesity. Obes Res 2005; 13: 491–500.
Peters JH, Simasko SM, Ritter RC . Modulation of vagal afferent excitation and reduction of food intake by leptin and cholecystokinin. Physiol Behav 2006; 89: 477–485.
Rolls BJ, Fedoroff IC, Guthrie JF . Gender differences in eating behavior and body weight regulation. Health Psychol 1991; 10: 133–142.
Smeets PA, de Graaf C, Stafleu A, van Osch MJ, Nievelstein RA, van der Grond J . Effect of satiety on brain activation during chocolate tasting in men and women. Am J Clin Nutr 2006; 83: 1297–1305.
Goetzman ES, Tian L, Nagy TR, Gower BA, Schoeb TR, Elgavish A et al. HIV protease inhibitor ritonavir induces lipoatrophy in male mice. AIDS Res Hum Retroviruses 2003; 19: 1141–1150.
Burton-Freeman B . Sex and cognitive dietary restraint influence cholecystokinin release and satiety in response to preloads varying in fatty acid composition and content. J Nutr 2005; 135: 1407–1414.
Niederau C, Meereis-Schwanke K, Klonowski-Stumpe H, Herberg L . CCK-resistance in Zucker obese versus lean rats. Regul Pept 1997; 70: 97–104.
Acknowledgements
We are grateful to Ivan Jenkins for greenhouse help and Reni Pouleva for technical assistance with cell culture. The analyses were supported in part by P50AT002776-01 grant from the National Center for Complementary and Alternative Medicine (NCCAM) and Phytomedics Inc (Jamesburg, NJ, USA).
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Komarnytsky, S., Cook, A. & Raskin, I. Potato protease inhibitors inhibit food intake and increase circulating cholecystokinin levels by a trypsin-dependent mechanism. Int J Obes 35, 236–243 (2011). https://doi.org/10.1038/ijo.2010.192
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DOI: https://doi.org/10.1038/ijo.2010.192
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