Sugar-reduced consumables containing hesperetin

Abstract

The present invention, among others, relates to a method for reducing consumption of sweet food, or reducing demand or desire for sweet food, of a human or animal subject, comprising: providing a consumable comprising a caloric carbohydrate and Hesperetin to the subject for consumption, wherein the subject has a low sweet taste threshold.

Description

Sugar-reduced consumables containing HesperetinFull DescriptionField of the InventionThe present invention relates to sugar-reduced consumables that are suited to reduce consumption of sweet food and / or reducing demand or desire for sweet food, and corresponding methods and uses. Background of the InventionIn order to increase healthiness of sweetened food, reduction of caloric sugar is mandatory. On the other hand, sweetness has to be on the same level as for the full sugar version to maintain consumer liking. Some sweeteners show similar metabolic effects as carbohydrates. Therefore, it is an object of the present invention to develop isosweet formulations which i) have lower caloric load and ii) no or positive effects on carbohydrate metabolism. In particular, the formulations should be able to reduce cravings for sweet food.Summary of the InventionThe present invention seeks to solve this object.According to a first aspect of the present invention, a method for reducing consumption of sweet food, or reducing demand or desire for sweet food, of a human or animal subject, comprises the step: providing a consumable comprising a caloric carbohydrate and Hesperetin to the subject for consumption, wherein the subject has a low sweet taste threshold.According to a second aspect of the present invention, a method for reducing energy intake, or reducing demand or desire for energy intake, by a human or animal subject, comprises the step: providing a consumable comprising a caloric carbohydrate and Hesperetin to the subject for consumption.The term “caloric carbohydrate” as understood herein means a carbohydrate providing a caloric load of at least 1 kcal / g, preferably at least 1.5 kcal / g, more preferably at least 2.0 kcal / g. It may encompass one or more monosaccharides, one or more disaccharides, and mixtures of one or more monosaccharides and one or more disaccharides. Preferred examples of caloric carbohydrates include sucrose, glucose, fructose, HFCS and combinations of two, three, or four thereof. Most preferably, the caloric carbohydrate included in the consumables of the present invention comprises or consists of sucrose.The present invention is based on the innovation of the inventors that consumables containing at least 30 % less caloric carbohydrates, in particular sucrose, glucose, fructose, and / or HFCS, compared to a regular (full sugar) formulation and Hesperetin in amount to reach isosweet taste compared to the regular (full sugar) formulation, prevent unfavorable metabolic states and can lead to mitigated food intake. Advantageously, the consumables of the present invention are able to mitigate appetite, energy intake, and metabolic impact of carbohydrates. They lead to decreased insulin peak, and increased satiation hormone levels. While the experiments described herein show that the postprandial increase of peak blood glucose level is not significantly altered by replacing the sweetness of a portion of the caloric carbohydrate by Hesperetin, the blood glucose levels do not fall as low afterwards. The drop below the baseline value is associated with craving. Therefore, the consumables of the present invention are associated with reduced craving for further sweet food stuff.Surprisingly, the effect is more pronounced in persons with a higher sweet taste threshold, which have been previously associated with a higher physical activity level. The consumables of the invention may therefore show the greatest benefits in athletics. Thus, the present invention provides consumables that are capable to reduce cravings for sweet food in persons belonging to the low sweet taste threshold group. The effects underlying the present invention are supported by studies comparing the effects of a 10% full sugar formulation (full sugar formulation) with those of a 7% reduced sugar formulation complemented with Hesperetin to similar sweetness levels (reduced sugar formulation). The inventors observed that following intake, persons of the high sweet taste threshold group indeed had a reduced energy intake after consumption of the Hesperetin containing reduced sugar formulation in comparison to the full sugar formulation. But surprisingly, only persons belonging to the low sweet taste threshold group, but not the high sweet taste threshold group, had lower cravings for sweet tasting food after consumption of the Hesperetin containing reduced sugar formulation in comparison to the full sugar formulation, alongside less insulin release. Accordingly, consumables of the invention are specifically able to reduce cravings for sweet food in persons belonging to the low sweet taste threshold group.The expression “low sweet taste threshold” as understood herein means a sweetness detection threshold lower than that of the average population. For example, the average sucrose detection threshold is 4.32 g / L. Accordingly, the low sweet taste threshold for sucrose means less than 4.32 g / L. The average detection thresholds for other carbohydrates can be determined by tasting, e.g. following the protocol disclosed in Breslin PAS, Izumi A, Tharp A, Ohkuri T, Yokoo Y, Flammer LJ, et al. (2021) Evidence that human oral glucose detection involves a sweet taste pathway and a glucose transporter pathway. PLoS ONE 16(10): e0256989. https: / / doi.org / 10.1371 / journal.pone.0256989. For instance, a mean threshold value of 13.3 mM was determined for glucose. The sweet taste receptor is known to not only be present in the oral cavity, but also in the gastrointestinal tract, where it contributes to the release of hormones that regulate energy intake and glucose metabolism. This regulation is driven by an interplay of the sweet taste receptor with glucose transporters. The inventors hypothesize that persons with a higher sweet taste threshold are also less sensitive regarding their gastrointestinal sweet taste receptors, and that glucose transporters are more important for this subgroup of people in the regulation of appetite, energy intake and glucose homeostasis. If the amount of sugar of a consumable is reduced, but the sweetness is maintained, this high threshold subgroup may benefit more, because in more sensitive persons, the sweet taste receptor might compensate for the reduced glucose-transporter activation.In a preferred embodiment of the present invention, the energy intake is selected from the group consisting of intakes of carbohydrates, sugars, fats and combinations thereof. A particular preferred effect of the consumables of the invention is on the energy intake in the form of carbohydrates.In contrast to the influence of the consumables of the invention on the consumption, demand or desire for sweet food, no differences in sugar intake between threshold groups have been observed. Therefore, the subject in embodiments of the method for reducing energy intake, or reducing demand or desire for energy intake, may belong to the high sweet taste threshold group, or to the low sweet taste threshold group.Corresponding to the meaning of “low sweet taste threshold” the expression “high sweet taste threshold” as understood herein means a detection threshold higher than average, e.g., higher than 4.32 g / L for sucrose.In preferred methods of the invention, the caloric carbohydrate is contained in amount of at least 30% less compared to a regular (full sugar) formulation, and the Hesperetin is contained in an amount to reach isosweet taste compared to the regular (full sugar) formulation. With current efforts of the food industry to reduce sugar content, it is clear that the meaning of what is considered regular is not a constant dimension, but subject to the spirit of the times. To make an example, sugar formulations that are nowadays considered as regular would have been considered as reduced sugar formulations in the past. Moreover, the amount of caloric carbohydrates usually differ across different types of preparations (e.g., beverages, yoghurts). Therefore, it is not possible to give specific values herein. However, the food industry has a common understanding of what is considered as a regular (full sugar) formulation at the time of interest. Therefore, the skilled person is able to determine the amount of the caloric carbohydrate in regular (full sugar) formulations for a specific type of preparation and at a specific time of interest.The amount of Hesperetin in the consumables of the invention is preferably sufficient to activate taste receptors, if consumed without caloric carbohydrate. The threshold for activation of the sweet receptor can be determined in vitro in a HEK system, or in vivo by sensor analysis, the latter being preferred. In vivo the threshold value for Hesperetin was found to be approx. 10 ppm, the EC50 is approx. 100 ppm.Further with respect to the amounts of constituents of the consumables of the invention, the Hesperetin may be contained in an amount ranging from 10 to 100 ppm, preferably 15 to 90 ppm, more preferably 20 to 80, more preferably 25 to 75 ppm, yet more preferably 30 to 70 ppm, most preferably 40 to 60 ppm. In specific consumables of the present invention, the caloric carbohydrate may range from 1.5 to 20 %, preferably 1.5 to 17 %, more preferably 2 to 14 %, more preferably 3 to 12 %, most preferably 3 to 10 %. In particular specific preparations, the caloric carbohydrate and the Hesperetin are contained in a weight ratio ranging from 150:1 to 20.000:1, preferably 167:1 to 11.333:1, more preferably 250:1 to 7.000:1, most preferably 400:1 to 4.800:1.The consumables may be provided in a serving size of, e.g., 100 mL to 500 mL, preferably 150 mL to 400 mL, more preferably 200 mL to 350 mL. Other serving sizes such as 30 to 100 mL are possible, too.The consumables in preferred embodiments of the invention are provided for consumption in the morning and / or after getting up. Thereby, the desire for sweetness and / or energy intake is suppressed directly at the start of the day. The consumables may be provided for consumption not only once, but also two times, three times, four times, five times, or six times. A third aspect of the present invention pertains to the use of Hesperetin for reducing consumption of sweet food, or reducing demand or desire for sweet food, of a human or animal subject having a low sweet taste threshold.A fourth aspect relates to the use of Hesperetin for reducing energy intake, or reducing demand or desire for energy intake, by a human or animal subject.A preferred use reduces energy intake, or demand or desire for energy intake, in the form of carbohydrates, sugars, fats and combinations thereof. Moreover, the subject provided with the consumables of the invention with the aim to reduce energy intake, or demand or desire for energy intake, may have a high sweet taste threshold or a low sweet taste threshold.The Hesperetin is preferably provided in the form of a consumable as described herein.It is further preferred that the use involves providing a consumable further comprising a caloric carbohydrate as described herein.Fifth and sixth aspects of the present invention pertain to therapeutic use and non-therapeutic use, respectively, of Hesperetin for activating PPAR signaling and / or TAS1R3 activation.Finally, novelconsumables comprising a caloric carbohydrate and Hesperetin are disclosed. The term “consumable” as used herein refers to goods that are intended to be consumed orally. Accordingly, consumables belong to the group of food including groceries like fruits, vegetables, dairy products, and grains, or beverages including water, soft drinks, juices, tea, coffee, and alcoholic beverages.A wide variety of food and beverages contain sugar, either naturally occurring or added during processing. These consumables are preferred targets of the present invention, meaning that a substantial portion of the sugar (e.g., 30 wt.-%) is replaced by small amounts of Hesperetin to reach isosweet taste. The consumables of the invention are thus preferably selected from the following types: Fruits: Many fruits naturally contain sugars, such as fructose. Examples include apples, oranges, bananas, grapes, and berries.Vegetables: Some vegetables, like carrots and beets, contain natural sugars.Desserts and Sweets: Cakes, cookies, pastries, ice cream, candies, and other sweet treats often have added sugars.Soft Drinks and Soda: Regular sodas and many soft drinks contain added sugars for sweetness.Fruit Juices: While fruit juices contain natural sugars, some commercially available juices also have added sugars.Breakfast Cereals: Many breakfast cereals, especially those marketed to children, contain added sugars.Dairy Products: Flavored yogurts, sweetened milk, and some ice creams may have added sugars.Baked Goods: Bread, muffins, and other baked goods can contain added sugars for flavor.Sauces and Condiments: Ketchup, barbecue sauce, and some salad dressings often have added sugars.Processed Foods: Many processed foods, including ready-made meals and snacks, may contain added sugars for taste.Energy Drinks: Some energy drinks contain added sugars to enhance flavor.Alcoholic Beverages: Cocktails, sweet wines, and some flavored spirits may contain added sugars.Sports Drinks: Some sports drinks have added sugars for taste and energy.Sweetened Teas and Coffees: Flavored teas, sweetened iced teas, and some coffee beverages can contain added sugars.Breakfast Bars and Snack Bars: Some granola bars and snack bars are sweetened with sugars.Specifically mentioned are sports drinks and meal replacement shakes. The consumables of the invention preferably contain Hesperetin in an amount ranging from 10 to 100 ppm, preferably 15 to 90 ppm, more preferably 20 to 80, more preferably 25 to 75 ppm, yet more preferably 30 to 70 ppm, most preferably 40 to 60 ppm. Additionally or alternatively, the consumables of the invention preferably contain a caloric carbohydrate in an amount ranging from 1.5 to 20 %, preferably 1.5 to 17 %, more preferably 2 to 14 %, more preferably 3 to 12 %, most preferably 3 to 10 %. Most preferred consumables contain the caloric carbohydrate and the Hesperetin in a weight ratio ranging from 150:1 to 20.000:1, preferably 167:1 to 11.333:1, more preferably 250:1 to 7.000:1, most preferably 400:1 to 4.800:1.The various features and embodiments described in relation to the first and second embodiments are to be understood to provide corresponding features and embodiments of the third and fourth aspects of the invention, and vice versa.Further aspects and embodiments of the present invention will arise from the experiments, which follow after the brief description of the drawings.Brief Description of the DrawingsThe drawings show:Fig. 1 Correlation between sweet liking and body fat [%]. Statistics: n = 32, non-parametric Spearman Correlation with two-tailed p-value.Fig. 2 Glucose concentration (mg / dL) corrected to baseline concentration between treatments S (10 % sucrose solution) and S + H (7 % sucrose solution + 50 mg / L Hesperetin). Values are depicted as mean ± SD, statistics: n = 32, two-way ANOVA with Sidaks Multiple Comparison Test. Asterisk * indicates significant difference with p <0.05.Fig. 3 A: Difference in area under the curve (AUC) of glucose concentrations between treatments S (10% sucrose solution) and S+H (7% sucrose solution + 50 mg / dL Hesperetin), values are depicted as mean, n = 32, unpaired t-test with two-tailed p-value. B: Differences in AUC of glucose concentrations between treatment S and S+H in low threshold group, statistics: n=17, paired t-test with two-tailed p-value. C: Differences in AUC of glucose concentrations between treatment S and S+H, in high threshold group, statistics: n = 15, paired t-test with two-tailed p-value.Fig. 4 Differences in minimum glucose concentration (mg / dL) between treatment S (10 % sucrose solution) and S+H (7 % sucrose + 50 mg / L hesperetin solution), values are depicted as mean, statistics: n = 32, paired t-test with two-tailed p-value, Fig. 5 Differences in minimum glucose concentration (mg / dL) between treatment S and S+H, comparison between low (A) and high threshold groups (B), values are depicted asmean, statistics: n = 32 (n per group = 15 – 17), paired t-test with two-tailed p-value.Fig. 6 A: Differences in Max / Min Ratio of AUC of glucose concentration between treatment S (10 % sucrose solution) and S+H (7 % sucrose + 50 mg / L Hesperetin solution), values are depicted as mean, statistics: n = 32, paired t-test with two-tailed p-value. B, C: Differences in Max / Min Ratio of AUC of glucose concentration between treatment between treatment S and S+H, comparison between low (B) and high (C) threshold groups, values are depicted as mean, statistics: n = 32 (n per group = 15 – 17), paired t-test with two-tailed p-value.Fig. 7 Correlation of desire for a sweet snack [mm] and minimal glucose concentration [mg / dL], non-parametric Pearson Correlation with two-tailed p-value, n = 64.Fig. 8 Differences in energy intake [kcal] (A), carbohydrate intake [g] (B), sugar intake [g] (C) and fat intake [g] (D) between treatments S (10 % sucrose solution) and S+H (7 % sucrose + 50 mg / L Hesperetin solution), values are depicted as mean + individual values, statistics: n = 32, paired t-test with two-tailed p-value.Fig. 9 Differences in energy intake (kcal) between treatments S and S+H, comparison between low (A) and high (B) threshold groups, values are depicted as mean +individual values, statistics: n = 32 (n per group = 15 – 17), paired t-test with two-tailed p-value.Fig. 10 Differences in sugar intake [g] (A), carbohydrate intake [g] (B) and fat intake [g] (C) between treatments S (10 % sucrose solution) and S+H (7 % sucrose + 50 mg / L Hesperetin solution), comparisons between low (left graphs) and high (right graphs) threshold groups, values are depicted as mean ± SD, statistics: n = 32 (15-17 per group), paired t-test with two-tailed p-value.Fig. 11 A: Correlation of FFQ score and liking score, non-parametric Spearman Correlation with two-tailed p-value, n = 32, B: Correlation of liking score and sugar intake (g), non-parametric Spearman Correlation with two-tailed p-value, n = 64.Fig. 12 Differences in appetite score between treatments S (10 % sucrose solution) and S+H (7 % sucrose + 50 mg / L Hesperetin solution), values are depicted as mean, statistics: n = 32, paired t-test with two-tailed p-value, Fig. 13 A: Differences in desire for a sweet snack between treatments S (10 % sucrose solution) and S+H (7 % sucrose + 50 mg / L Hesperetin solution), values are depicted as mean, statistics: n = 32, paired t-test with two-tailed p-value. B, C: Differences in desire for a sweet snack between treatments S and S+H, comparison between low (B) and high (C) threshold groups, values are depicted as mean ± SD, statistics: n = 32 (n per group = 15 – 17), paired t-test with two-tailed p-valueDetailed DescriptionExamplesA study was made in which the amount of sucrose was reduced from 10% to 7% while the sweetness was maintained by adding 50 mg / L (50 ppm) Hesperetin instead. This sugar reduced formulation was compared to a corresponding equi-sweet formulation comprising 10% sucrose and no Hesperetin. The design of the study was an open, randomized, controlled cross-over design with 31 to 35 healthy male participants (alpha=0.85, p<0.05). The participants had an age of 18 to 45 years, were metabolically healthy, had a body mass index (BMI) lower than 30 kg / m2 and body fat lower than 30%. The study population included in the analysis is summarized in the table below. Mean (min. – max.)N32 Age [years]27 (21 – 42)body height [m]1,81 (1,64 – 2,05)body weight [kg]77,6 (57,8 – 9 7,9)BMI [kg / m2]23,5 (18,5 - 28,6)body fat [%]16,54 (5,00 - 29,90)The results of the study are summarized below.A correlation between body fat and liking of sweet food was found (cf. Fig. 1). The correlation showed a trend that higher liking scores are associated with are associated with lower body fat. Additionally, participants with a body fat body below 12.5 % had a significantly higher liking for sweet food than subjects with a body fat higher than 21.0 %.When grouping the liking score into sweet and sweet-fatty foods, a higher body fat is only correlated with lower liking of sweet-fatty food, whereas no correlation with liking of sweet-only food can be observed. Referring tom Fig. 2, the glucose concentrations over time were physiologically normal. No differences in the maximum values between treatments were found despite different caloric load. At t=90 min, however, significantly higher glucose concentration after consumption of 7% sucrose plus Hesperetin (squares) as compared to the consumption of sucrose-only (circles) was found.Fig. 3 illustrates the Glucose Area under the curve (AUC). The consumption of sucrose together with Hesperetin resulted in lower AUC as compared to sucrose-only consumption. The effect comes mainly from the high threshold group.Moreover, blood sugar drop was reduced in the sucrose plus Hesperetin group as compared to the sucrose-only group. Minimum glucose concentration was higher after consumption of sucrose plus Hesperetin. Therefore, blood sugar did not drop as drastically as with 10% sucrose (cf. Fig. 4). In the low threshold group there was a trend for higher minimum glucose level after consumption of sucrose plus Hesperetin. However, the high threshold group did not drop as much as the low threshold group after 10% sucrose-only consumption (cf. Fig. 5).As shown in Fig. 6, fluctuations in blood sugar were generally decreased, as the difference between highest and lowest glucose value was lower after 7% sucrose plus Hesperetin consumption. This effect comes mainly from the high threshold group.A correlation between desire for a sweet snack and minimal glucose concentration was found. The higher the minimum glucose value, the lower the craving for a sweet snack (cf. Fig. 7).In conclusion, reducing the caloric load in a sucrose solution while maintaining sweetness by adding 50 mg / L Hesperetin led toA higher minimum glucose concentration;A lower difference in Max-Min Glucose concentrations —> decrease in glucose fluctuations; andA decrease in the subjective desire for a sweet snack: The higher the minimum glucose value, the lower the craving for a sweet snack.Reducing the caloric load in a sucrose solution while maintaining sweetness by adding 50 mg / L Hesperetin can reduce large fluctuations in blood sugar levels.Next, the effects on energy intake and appetite was evaluated.A reduced energy intake was observed in the 7% sucrose + Hesperetin treatment group. Specifically, there was a decreased intake of carbohydrates, sugar and a tendency for lower fat intake (cf. Fig. 8).The reduced energy intake existed mainly in the high threshold group (cf. Fig. 9).The type of nutrient intake between the threshold groups are illustrated in Fig. 10. As can be seen, the high threshold group showed a trend towards lower intake of carbohydrates and fat after 7% sucrose plus Hesperetin consumption. Notably, no differences in sugar intake between threshold groups was seen.When assessing the correlation between sugar intake from a standardized breakfast and liking for sweet food, it was found that sugar intake correlates with sweet liking score, but not with the reported intake of sweet tasting foods from a food frequency questionnaire (FFQ) (cf. Fig. 11). From this follows that the liking score is a good indicator of actual dietary habits.Finally, no differences in overall appetite score were determined (cf. Fig. 12). However, the desire for a sweet snack was lower after consumption of 7% sucrose plus Hesperetin. The effect comes mainly from the low threshold group (cf. Fig. 13).In conclusion, consumption of 7% sucrose plus Hesperetin leads to a decrease in energy intake as compared to consumption of 10% sucrose. The effect is mainly due to the high threshold group. Moreover, the sugar and carbohydrate intake decreases after consumption of 7% sucrose plus Hesperetin. A reduction in carbohydrate and fat intake after consumption of 7% sucrose plus Hesperetin occurs in the high threshold group.It could thus be shown that reducing the caloric load from sucrose while maintaining sweetness can decrease appetite and sweet cravings therefore, and reduce energy and sugar intake.

Claims

Claim 1. Method for reducing consumption of sweet food, or reducing demand or desire for sweet food, of a human or animal subject, comprising:providing a consumable comprising a caloric carbohydrate and Hesperetin to the subject for consumption,wherein the subject has a low sweet taste threshold. Claim 2. Method for reducing energy intake, or reducing demand or desire for energy intake, by a human or animal subject, comprising:providing a consumable comprising a caloric carbohydrate and Hesperetin to the subject for consumption.Claim 3. The method of claim 2, wherein the energy intake is selected from the group consisting of intakes of carbohydrates, sugars, fats and combinations thereof. Claim 4. The method of claim 2 or 3, wherein the subject has a high sweet taste threshold. Claim 5. The method of any of claims 1 to 4, wherein the caloric carbohydrate is contained in amount of at least 30% less compared to a regular formulation, and the Hesperetin is contained in an amount to reach isosweet taste compared to the regular formulation. Claim 6. The method of any of claims 1 o 5, wherein the Hesperetin is contained in an amount ranging from 10 to 100 ppm, preferably 15 to 90 ppm, more preferably 20 to 80, more preferably 25 to 75 ppm, yet more preferably 30 to 70 ppm, most preferably 40 to 60 ppm. Claim 7. The method of any of claims 1 to 6, wherein the caloric carbohydrate is contained in an amount ranging from 1.5 to 20 %, preferably 1.5 to 17 %, more preferably 2 to 14 %, more preferably 3 to 12 %, most preferably 3 to 10 %. Claim 8. The method of any of claims 1 to 7, wherein the caloric carbohydrate and the Hesperetin are contained in a weight ratio ranging from 150:1 to 20.000:1, preferably 167:1 to 11.333:1, more preferably 250:1 to 7.000:1, most preferably 400:1 to 4.800:

1. Claim 9. Method of any of claims 1 to 8, wherein the consumable is provided for consumption in the morning and / or after getting up. Claim 10. Use of Hesperetin for reducing consumption of sweet food, or reducing demand or desire for sweet food, of a human or animal subject having a low sweet taste threshold. Claim 11. Use of Hesperetin for reducing energy intake, or reducing demand or desire for energy intake, by a human or animal subject. Claim 12. The use of claim 11, wherein the energy intake is selected from the group consisting of intakes of carbohydrates, sugars, fats and combinations thereof. Claim 13. The use of claim 11 or 12, wherein the subject has a high sweet taste threshold. Claim 14. The use of any of claims 10 to 13, wherein the use involves providing a consumable comprising a caloric carbohydrate and Hesperetin to the subject for consumption and / or wherein the consumable is as defined in any of claims 5 to 8. Claim 15. Therapeutic or non-therapeutic use of Hesperetin for activating PPAR signaling.

Images