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Raspberry ketone is a major aromatic compound of red raspberry (Rubus idaeus). The structure of RK is similar to the structures of capsaicin and 
synephrine, compounds known to exert anti-obese actions and alter the lipid metabolism. Raspberry (European red raspberry, Rubus idaeus) is one of the oldest fruits known to people and has been used throughout the centuries for nutritional and medicinal purposes. Like its popular relatives the strawberry and blueberry, raspberry contains an abundance of sugars, vitamins, minerals, and polyphenols. Studies on the biological effects of raspberry components have yielded many results. In one study, for example, the ellagic acid in raspberries was confirmed to inhibit tumor inductions in the liver, lungs and esophagus (Ravai, 1996). Other work has been conducted to explore the makeup of the unique fragrance and flavor of raspberry by isolating various of its aromatic compounds. Raspberry ketone (4-(4-hydroxyphenyl) butan-2-one; Raspberry Ketone), one of the major aromatic compounds of raspberry (Gallois, 1982), is widely used as a fragrance in cosmetics and as a flavoring agent in foodstuffs (Guichard, 1982). In one study investigating the intragastric administration of RK (1 mmol/ kg), about 90% of the dose was excreted as metabolites via the urine within 24 h in rats, guinea pigs and rabbits (Sporstol and Scheline, 1982).
Before now, however, there have been no reports on the biological effects of Raspberry Ketones.
RASPBERRY KETONE TEST ON MICE
The study was performed to clarify whether Raspberry Ketone helps prevent obesity and activate lipid metabolism in rodents. To test the effect on obesity, 1) mice were fed a high-fat diet including 0.5, 1, or 2% of Raspberry Ketone for 10 weeks; 2) mice were given a high-fat diet for 6 weeks and subsequently fed the same high-fat diet containing 1% Raspberry Ketone for the next 5 weeks.
Dietary fat is digested by pancreatic lipase and absorbed from the small intestine (Verger, 1984; Hernell et al., 1990). In strategies to prevent obesity, one of the key steps is to inhibit the digestion and absorption of the dietary fat. To explore this strategy further, Raspberry Ketone was further studied on fat absorption. Raspberry Ketone at a concentration of 5% reduced the elevation of plasma triacylglycerol after oral administration of a lipid emulsion containing corn oil in rats, whereas a lower concentration of Raspberry Ketone 1% elicited no such effect (data not shown).
Moreover, Raspberry Ketone at concentrations of 1–20 mg/ml inhibited rat pancreatic lipase activity in an assay system using trioleoylglycerol emulsified with lecithin (Tsujita et al., 1996), whereas the same concentrations exhibited no such inhibitory effect when the trioleoylglycerol was emulsified with gum arabic instead of lecithin in the same system (data not shown). This means that the site of the inhibitory action of Raspberry Ketone on trioleoylglycerol hydrolysis may be the substrate rather than the enzyme. In any case, these results suggest that Raspberry Ketone suppresses the dietary fat absorption by inhibiting the trioleoylglycerol hydrolysis. Significantly, however, the inhibitory effect of Raspberry Ketone on fat absorption is not the main anti-obese mechanism. This is known because the minimum Raspberry Ketone dose required to exert these effects is much higher than that required to exert anti-obese effects.
Dietary sugars such as glucose and fructose are also known to increase hepatic lipogenesis and promote fat accumulation (Herzberg and Rogerson, 1988). Raspberry Ketone (1%) suppressed weight elevation in visceral and subcutaneous adipose tissues induced by the over-intake of fructose (Y. Morimoto, personal communication). Given that Raspberry Ketone reduces both fat- and sugar-induced fat accumulation, we postulated that its anti-obese action is conferred mainly during the stages of fat decomposition.
Based on these experiments, the effect of Raspberry Ketone was examined on lipolysis of white adipocytes. The catecholamines norepinephrine and epinephrine are known to stimulate lipolysis via beta-adrenergic receptor. Similarly, synephrine can activate in vitro lipolysis in rat adipocytes via activation of the same receptor (Carpene et al., 1999). This prompted the examination of the effect of Raspberry Ketone on lipolysis in rat epididymal fat cells and the ability of RK to bind various subtypes of beta-adrenergic receptors. While Raspberry Ketone failed to stimulate lipolysis in the absence of norepinephrine and failed to bind to beta 1, 2 and 3- adrenergic receptors (data not shown), it was successful in increasing norepinephrine-induced lipolysis at the concentration of 10–3 M (Fig. 5A). We find it noteworthy that RK has a lipolytic activity that takes place via a mechanism unrelated to that of synephrine. Noting that the rate-limiting step in lipolysis in fat cells, the hydrolysis of triacylglycerol, is catalyzed by HSL (Khoo et al., 1976; Belfrage et al., 1984), we decided to examine the effect of Raspberry Ketone on HSL activity in rat fat cells. We found that Raspberry Ketone did not enhance the HSL activity at the concentration of 10-3 M (data not shown). In another paper is was reported that the conversion of the HSL translocation to its substrate on the surfaces of lipid droplets is a crucial step for triacylglycerol hydrolysis (Morimoto et al., 1999, 2001). The localization of HSL in fat cells was examined and Raspberry Ketone at a concentration of 10-3 M significantly increased the amount of HSL protein in the fat layer and concomitantly reduced that in the supernatant (Fig. 5B, C). These results suggest that Raspberry Ketone enhances norepinephrine-induced lipolysis not via the HSL activation, but via an increase in the translocation of HSL from the cytosol to the lipid droplets in the fat cells.
Capsaicin was reported to exert anti-obese activity by enhancing the energy metabolism (Kawada et al., 1986a, b). This effect might be due to an increase of thermogenesis in brown adipose tissues (BAT) through the stimulation of the sympathetic nervous system (Watanabe et al., 1994). If this is so, we can speculate that Raspberry Ketone also stimulates the energy metabolism via a mechanism similar to that capsaicin. Capsaicin administration increases the oxygen consumption in rats (Kawada et al., 1986b), while Raspberry Ketone supplementation increases the oxygen consumption and reduces the respiratory quotient (R.Q.) in rats (T. Shimazu, personal communication). In another study, the effect of Raspberry Ketone on energy metabolism was examined by measuring cytochrome c oxidase activity in mouse BAT. Both the specific activity and total activity of cytochrome c oxidase activity were significantly increased by Raspberry Ketone (Y. Morimoto, personal communication). These results indicate that Raspberry Ketone activates the BAT thermogenesis and enhances the energy metabolism. In any case, more detailed studies in the future should help clarify the mechanisms by which Raspberry Ketone enhances energy metabolism.
In conclusion, the present investigation demonstrated that Raspberry Ketone has an anti-obese function. Raspberry Ketone stimulated the metabolism of white Raspberry Ketone might exert its anti-obesity effect via an increase of norepinephrine-induced lipolysis in white adipocytes and an enhancement of thermogenesis in BAT (brown adipose tissue).
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