When does sucrose increase appetite and adiposity?

Appetite, 1987, 9, 1-19

When Does Sucrose Increase Appetite and Adiposity?

ISRAEL RAMIREZ Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104

Two methods of sucrose feeding have been employed in studies with rodents. In the nutritional method, part or all of the starch in a diet is replaced with sucrose. In the solution method, animals maintained on a nutritionally complete diet are given a sucrose solution to drink. The solution method is generally a more effective and reliable method of producing obesity except for weanling rodents. These two methods yield different results with regard to interactions with the fat and protein content of the diet, efficiency of weight gain, disaccharide effects and effects of meal feeding. It is suggested that for the nutritional method, sucrose alters food intake and adiposity via its effects on fat oxidation. For the solution method, the critical factor may be presenting a wet source of calories rather than sucrose per se. Differences in the way sucrose is fed do not account for all divergent results. Different investigators conducting similar experiments have often obtained different results. For these and other reasons, animal studies do not support the idea that sucrose intake causes obesity in humans.

It is widely believed that consumption of sucrose may predispose human beings to obesity. This idea has been discussed in scientific publications (e.g. Fullerton, Getto, Swift & Carlson, 1985; Geiselman & Novin, 1982) and in popular works (e.g. Shell, 1985; Yudkin, 1972). It is therefore surprising that no comprehensive reviews of the effects of sucrose on appetite or adiposity can be found except for a brief and incomplete review (Bender & Damji, 1971). Since humans consume substantial amounts of sucrose (Anderson, 1982), it is appropriate to inquire whether there is any justification for blaming sucrose for obesity. Any such inquiry should begin with a scrutiny of previous research. The purpose of the present review is to evaluate animal research concerning sucrose and obesity.

PRELIMINARY CONSIDERATIONS

The present review focuses on rats and mice. This reflects the author’s opinion that controlled studies in rodents are most likely to yield information about the mechanisms by which sucrose affects appetite and adiposity. A section of this review discusses the applicability of animal research to humans. The present review is also limited to

This work was supported by a National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases grant AM-34375.

Comments from Mary Bertino, Michael Tordoff, Mark Friedman and Anne Ramirez improved this manuscript.

Requests for reprints should be addressed to: Israel Ramirez, Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104, U.S.A.

0195~6663/87/.040001+ 19 $03.00/O ((7 1987 Academic Press Limited

2 I. RAMIREZ

experiments lasting longer than one day. While effects that appear in brief tests may provide useful clues about the regulation of appetite, it is likely that only effects that appear over many days can significantly affect adiposity.

The ideal study would be one in which animals were given nutritionally adequate diets that differed only in the relative proportion of sucrose to starch. In the present review this is called the “nutritional method”. In the author’s opinion, this is the only kind of approach that can unambiguously establish an effect of sucrose. Some studies have compared diets composed of various grains and other complex nutrients (“chow” or “stock” diets) to semisynthetic diets containing sucrose. The latter type of experiment has been excluded because it is impossible to tell whether sucrose or some other factor is responsible for any differences between animals fed such diets.

A large number of studies have been conducted in which animals were fed a complete solid diet with or without a sucrose solution. In the present review, this is called the “solution method”, An advantage of this method is that animals can select the proportion of sucrose calories that they prefer to ingest. However,,the experimenter has less control over how much sucrose is ingested. Furthermore, changes in sucrose consumption usually result in changes in consumption of protein, fat, fiber, minerals and vitamins. One of the purposes of this review is to suggest that the changes in appetite and obesity seen when sucrose solutions are offered are not due to sucrose per se.

A wide variety of measures of adiposity have been used. The most common methods are weights of selected adipose tissue depots (usually gonadal and/or retroperitoneal) or total body fat content; sometimes the results have been expressed as the ratio of fat weight to total animal weight. The present review does not attempt to evaluate the appropriateness of most such measures. Body water cannot be used as an index of obesity because two studies presented data indicating that body water correlates poorly with body fat (Al-Nagdy, Miller & Yudkin, 1970; MacRae, Nickel, Slinger & Neudoerffer, 1974 b). Liver fat content has not been used as an index of adiposity. For the purposes of this review, obesity is defined as any increase (compared to controls) in body fat or per cent body fat. Similarly, overweight is defined as any increase in total body weight.

The title reflects the reviewer’s assumption that obesity is correlated with altered appetite; an assumption which may be disputed (Slattery & Potter, 1985). Sucrose might increase obesity without affecting food intake by increasing energetic efficiency or by reducing lean body mass. Energetic efficiency has been assessed in a number of studies, usually by computing weight gain divided by calories consumed. This method is inadequate; the appropriate method is to calculate the increase in body energy content and divide by caloric intake (Rothwell & Stock, 1984). Since completely satisfactory studies are rare, data on efficiency of weight gain are described without any criticism of methodology.

NUTRITIONAL METHOD

Comparisons of rodents fed diets containing sucrose vs. starch have produced inconsistent results (see Table 1). Sometimes sucrose feeding increased weight gain, adiposity, and food intake, whereas sometimes the reverse effects were found. Counting positive and negative findings suggests that sucrose feeding leads to obesity more often than not (see counts in Table 1). Counting the studies in Table 1 also leads to the

SUCROSE 3

surprising conclusion that sucrose in the diet does not usually increase food intake. Table 1 must be interpreted cautiously because of a probable tendency of experimen- ters to publish more papers when sucrose shows positive effects than when sucrose has no effect. Individual laboratories tend to obtain similar results upon replication, resulting in a bias toward positive results in the literature.

Table 1 does not include all studies of the effects of sucrose compared to starch feeding. Studies in which the results were equivocal or in which the feeding period was shorter than two weeks were excluded. Older studies on the interactions between sucrose and essential nutrients have not been adequately represented; fortunately this literature has been reviewed by Harper & Elvehjem (1957). The net effect of eliminating such studies is to slightly underrepresent studies showing that sucrose has no or negative effects.

Variables Influencing Results

Many of the studies included in the table involve weanling rats. The age of the animals in studies using the nutritional method does not seem to be an important factor except for low-protein diets. One group of investigators obtained similar results with weanling and mature rats (Al-Nagdy, Miller, Qureshi & Yudkin, 1966; Al-Nagdy et al., 1970). Moser and Berdanier (1974) found that the type of carbohydrate fed from weaning up to 50 days of age did not affect subsequent growth response to sucrose or starch diets. On the other hand, interactions between type of carbohydrate and essential nutrients are likely to be greater for immature rats because their nutritional needs are so great (Harper & Elvehjem, 1957).

Sucrose does not produce obesity when the diet is low in protein (Marshall, Hildebrand, DuPont & Womack, 1969). Indeed, low-protein (9-l 1%) high-sucrose diets usually reduce weight gain, food intake and adiposity when fed to weanling rats but not when fed to adult rats (Harper & Katayama, 1953; Harper, Monson, Arata, Benton & Elvehjem, 1953; Harper & Spivey, 1958; Romberg & Benton, 1965; Weiner et al., 1963). This effect of sucrose seems to be due to reduced food intake (Weiner, Yoshida & Harper, 1963); pair feeding eliminates this effect (Harper et al., 1953). Conversely, for adequate protein diets, sucrose induced obesity is sometimes partly due to increased energetic efficiency-that is, an increased ratio of body weight or calories in the carcass to calories consumed (Back & Angel, 1982; Marshall et al., 1959). Indeed, sucrose-fed rats may show greater weight gain than starch- or glucose-fed rats even when the sucrose-fed rats are prevented from overeating (Feyder, 1935; MacRae et al., 1974 b). Only rarely does sucrose reduce energetic efficiency (Williams & Szepesi, 1983).

A number of nutritional studies tested the effects of meal feeding, limiting food intake to one to three hours a day. Meal feeding usually exaggerates sucrose enhancement of growth and appetite (Gardner & Michaelis, 1979; Jorgensen, Hallfrisch & Reiser, 1978; Michaelis, Scholfield, Gardner & Cataland, 1980; Reiser & Hallfrisch, 1977), although Harper and Spivey (1958) did not observe such an effect. This result is surprising because the greater osmotic pressure of sucrose compared to starch in the stomach would lead one to predict that sucrose ought to decrease rather than increase food intake in meal-fed rats (Harper & Spivey, 1958). The mechanisms mediating this meal feeding effect merit more attention.

Most nutritional studies involve rather extreme changes in diet; typically all of the carbohydrate is either sucrose or corn starch. MacRae et al. (1974 b) found that a diet containing as little as 40% sucrose stimulated weight gain, although 62% of the

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6 I. RAMIREZ

carbohydrate was sucrose. Other studies suggest that large amounts of sucrose are needed to produce any effect. Cohen and Teitelbaum (1964) used diets containing 33,40 and 67% sugar; only the 67% sugar diet reliably reduced weight gain. Laube, Wojcikowski, Shatz & Pfeiffer (1978), found no significant differences in body weight among rats fed diets containing 20, 50 or 70% sucrose. Naim, Brand, Kare and Carpenter (1985) found that feeding rats 25% sucrose diets had no reliable effects on food intake, weight gain, or obesity. Nearly all studies reporting significant effects of sucrose on weight, obesity, or food intake used diets containing at least 40% of total calories as sucrose. This issue is important because human beings do not usually ingest diets as high in sucrose as have been fed to rats (Anderson, 1982).

Other Sugars

Theoretically, comparisons of sucrose with other sugars can give some clues about the mechanism of action of sucrose. If, for example, glucose diets produce effects similar to those observed with sucrose, then it may be inferred that the fructose component of sucrose is not necessary. In practice, such studies have not been as enlightening as might be desired.

Diets using glucose as the carbohydrate source may induce less weight gain than sucrose diets (Allen & Leahy, 1966; Berdanier, 1974; Feyder, 1935; MacRae et al., 1974a,b; Williams & Szepesi, 1983), similar weight gain (MacRae et al., 1974a; Waterman, Romsos, Tsai, Miller & Leveille, 1975) or even greater weight gain (Winand & Christophe, 1977). It is difficult to evaluate reports on the effects of glucose feeding on food intake because it is not always clear whether hydrous or anhydrous glucose was used, making it difficult to compute caloric intake. In two studies, fructose-containing diets resulted in food intake and weight gains similar to that seen with sucrose- containing diets (Allen & Leahy, 1966; Reussner, Andros & Thiessen, 1963). However, Winand and Christophe (1977), MacRae et al. (1974a) and Waterman et al. (1975) found that high-fructose diets produced less weight gain than high-sucrose diets.

Some evidence suggest that disaccharides (e.g. maltose and sucrose) have greater effects than monosaccharides (e.g. glucose and fructose). Maltose containing diets produce weight gains, food intake, and adiposity as great as or possibly greater than that produced by diets containing sucrose (Michaelis et al., 1978; Reussner et al., 1963; Williams & Szepesi, 1983). An even more suggestive finding is that sucrose based diets sometimes produce greater weight gain or adiposity than diets containing glucose and fructose in equimolar amounts (Michaelis et al., 1978, 1980, 1981; Williams & Szepesi, 1983), although Laube, Klor, Fussganger and Pfeiffer (1973) did not find such an effect. The disaccharide effect provides a valuable clue about the mechanism for sucrose- induced obesity; this matter is discussed in the section on mechanisms.

Can Contradictory Results be Explained?

It is possible that sucrose interacts with other components of the diet in nutritional studies. As described above, level of dietary protein is one such factor, although large changes in protein content of the diet sometimes do not alter the results appreciably (Al-Nagdy et al., 1966; Cohen & Teitelbaum, 1966). Type of protein used does not seem to be a major factor when due allowance is made for differences in protein quality; greater amounts of low quality proteins are needed to promote growth. One group of researchers observed reduced growth and appetite in rats fed sucrose diets containing

SUCROSE 7

casein, fibrin, egg albumin, soyabean protein, wheat gluten and a mixture of amino acids (Harper et al., 1953; Weiner et al., 1963). On the other hand, Marshall et al. (1969) found that sucrose diets containing either lactalbumin or wheat gluten increased weight gain and adiposity.

Type of starch and percentage of carbohydrate in the diet might influence the results obtained, but nearly all researchers used corn starch and SO-SO% carbohydrate. There appear to be slight differences between cooked and raw cornstarch but these differences are not large enough to account for the discrepancies among different studies (Harper & Katayama, 1953; Reussner et al., 1963).

The amount of dietary fat does not seem to be an important factor. In one study, sucrose stimulated growth when the diet contained either 3 or 15% fat (Marshall et al., 1959). Hallfrisch, Cohen and Reiser (1981) observed that greater obesity was produced when their 40% fat diet contained sucrose rather than starch. Naim et al. (1985) did not find any reliable effects of using sucrose in either high- or low-fat diets.

The type of carbohydrate used influences nutritional requirements for certain vitamins, apparently by altering growth of intestinal microflora (Harper & Elvehjem, 1957). It is worth noting that although commercial sucrose is a highly purified product, corn starch is not. Corn starch contains significant amounts of free fatty acids (Subcommittee on Laboratory Animal Nutrition, 1978) and much more ash than sucrose (Ramirez, unpublished work). Since investigators have used a wide variety of vitamin and mineral mixes in their diets, it is possible that some investigators used diets which are nutritionally adequate when one carbohydrate is used, but not adequate when another carbohydrate is used.

It might be that different investigators used different strains of rats and mice which respond differently to sucrose. There are reports that two of the most commonly used strains of rats, Wistar and BHE, differ from each other in response to sucrose and starch diets (Berdanier, Tobin & DeVofe, 1979; McCusker, Deaver & Berdanier, 1983). In order to determine why different strains give different results, it will first be necessary to identify the physiological and biochemical effects of sucrose which increase and decrease food intake, body weight and adiposity.

It must be concluded that, at present, it is not possible to say why published studies using the nutritional method have been so inconsistent. The most promising variables to investigate in future studies would seem to be heredity and micronutrients.

SOLUTION METHOD

No attempt has been made to cite all or even most studies employing the solution method because the purpose of this section is to compare studies using the solution method to others employing the nutritional method.

Studies employing the solution method usually show that sucrose increases caloric intake, weight gain and adiposity (Kanarek & Hirsch, 1977). Rats given sugar solutions reduce intake of solid food, partially compensating for the calories from the sugar. Early studies emphasized this compensation even though total caloric intake was slightly elevated by sugar availability (Collier & Bolles, 1968; Hausmann, 1933; Rytand, 1~943). Kanarek and Hirsch (1977) were apparently the first researchers to realize that offering rats sugar solutions provided a potentially useful animal model of obesity.

8 I. RAMIREZ

Studies using the solution method are similar to those using the nutritional method in one important respect: in most cases the percentage of calories from sucrose is usually high. However, the percentage is variable between experiments; values as high as 67% (Bukowiecki, Lupien, Follea & Jahjah, 1983) and as low as 20% (Trout, Moy, Putney & Johnson, 1978) have been reported in studies in which sucrose increased caloric intake and adiposity.

Negative results can be summarized fairly easily. It appears to be difficult to produce obesity by feeding sucrose solutions to weanling rats (Hirsch, Dubose & Jacobs, 1982; Muto & Miyahara, 1972; Rothwell 8z Stock, 1984). However, even in weanling rats, slightly increased adiposity can be shown by carcass analysis (Kanarek & Marks-Kaufman, 1979). One strain of rats (S 5B/Pl) that is resistant to other kinds of dietary obesity is also resistant to sucrose solution obesity (Schemmel et al., 1982). There are a few reports that availability of sucrose solution had no effect on total caloric intake (Kenney & Collier, 1976; Friedhoff, Simon & Friedhoff, 197 1; Teague, Kanarek, Bray, Glick & Orthen-Gambill, 1981) and two reports that sucrose had no effect on caloric intake although it increased weight gain (Hill et al., 1980, Sclafani & Xenakis, 1984 a, b). These failures to find differences are rare.

There are only three situations in which sugar solutions seem to significantly decrease total caloric intake and body weight. Providing a sucrose (Hamilton, 1971) or glucose (Sclafani, 1973) solution to meal-fed rats during the meal can result in substantial weight loss and even death. Presentation of sucrose solution to rats fed high-fat diets resulted in either no change in body weight and adiposity (40 and 60% fat diets) or even reduced weight and adiposity (80% fat diet, Rattigan & Clark, 1984). When weanling rats are fed a low-protein diet, presentation of a sucrose solution can reduce caloric intake and growth (Muto & Miyahara, 1972). The first two findings are interesting because they are completely contrary to what has been found for the nutritional method (see above).

Degree of Obesity

Sclafani (1978) and Sclafani and Xenakis (1984a) suggested that the solution method is a more effective method of producing obesity than the nutritional method. In order to verify this claim, I selected all available studies in which feeding sucrose ad libitum increased adiposity. A simple index was used to assess the degree of obesity produced, the ratio of adiposity of sucrose-fed to adiposity of control animals. In studies reporting more than one measure of adiposity, the ratios for different measures were averaged. Only groups fed ad libitum and showing a positive and statistically significant effect were used. Nine studies reported that feeding sucrose solution increased body fat content (Bukowiecki et al., 1983; Faust, Johnson, Stern & Hirsch, 1978; Granneman & Wade, 1983; Kanarek & Marks-Kaufman, 1979; Kanarek & Orthen-Gambill, 1982; Trout et al., 1978; Rattigen & Clark, 1984; Schemmel et al.. 1982; Vasselli, Haraczkiewicz & Pi-Sunyer, 1982). The average ratio is 1.65 kO.13 with a range of 1.12 to 2.26. Thirteen studies reported that ad Zibitum feeding of sucrose- based diets increased body fat (Bhathena, Revett, Michaelis, Ellwood, Voyles & Recant, 1986; Hallfrisch et al., 1978,198l; Gardner 8z Michaelis, 1979; Jorgensen et al., 1978; Laube et al., 1973; Marshall et al., 1959, 1969; Michaelis et al., 1980, 1983, 1986; Reiser & Hallfrisch, 1977; Williams & Szepesi, 1983). The average ratio of sucrose fed to

SUCROSE 9

control rats for these studies is 1.31 kO.03 with a range of 1.17 to 1.57. A Mann-- Whitney U test indicated a significant effect of method of feeding sucrose (U = 25, p <O-05). This analysis minimized the difference between the two methods because groups showing no effect of ad libitum sucrose on adiposity were excluded; this occurred more often for the nutritional (11 times, see Table 1) than for the solution method (three times, Muto & Miyahara, 1972; Rattigan & Clark, 1984; Schemmel et al., 1982). It seems safe to conclude that the solution method produces more severe obesity than does the nutritional method.

That sucrose solution availability can produce obesity at all is surprising for two reasons. First, offering a sucrose solution increases energy expenditure (Rothwell & Stock, 1984). This is probably due to increased size and/or the metabolic activity of brown adipose tissue (Bukowiecki et al., 1983; Granneman & Wade, 1983; Kanarek & Orthen-Gambill, 1982; Teague et al., 1981; Rothwell & Stock, 1984) as well as increased activity of Na,K-ATPase (Flier et al., 1981). Increased thermogenesis resulting from feeding a sucrose solution decreases efficiency of weight gain (Bukowiecki et al., 1983; Granneman & Wade, 1983). These metabolic changes would lead one to expect reduced rather than increased weight gain and adiposity. This evidence for decreased metabolic efficiency sharply contrasts with results obtained with the nutritional method which suggest that sucrose feeding increases efficiency of weight gain (see above).

Secondly, offering a sucrose solution in addition to solid food results in reduced intake of protein and other essential nutrients. For example, Kanarek and Hirsch (1977) estimated that animals given sucrose solutions consumed only 10% of their calories in the form of protein whereas control rats consumed a 23% protein diet. Sucrose solution availability can increase total caloric intake even when the solid diet contains as little as 5% protein (Castonguay, Rowland & Stern, 1985). Given the nutritional studies showing that low protein intake reduces food intake and weight gain of sucrose-fed rats, it is remarkable that offering a sucrose solution is such a good method of producing obesity.

Other Sugars

Studies using the nutritional method tend to show that different sugars produce different results; disaccharides tended to produce greater weight gain and adiposity then monosaccharides (see above). Studies using the solution method reliably show that glucose and sucrose produce similar results (Castonguay & Hirsch, 1981; Kanarek & Orthen-Gambill, 1982; Trout et al., 1978). Only one study compared fructose and sucrose solutions; in this case fructose had the same effects on total caloric intake and obesity as sucrose and glucose (Kanarek & Orthen-Gambill, 1982). However, less fructose solution was consumed than sucrose solution. Another study compared fructose and glucose solutions but did not include control rats given no solution; weight gain was unaffected by the type of sugar in the solution given to four strains of rats (Aoyama et al., 1980). There is no evidence for a disaccharide effect in any study using the solution method; monosaccharides such as glucose and fructose have the same effects as sucrose.

Surprisingly, allowing rats to drink polysaccharide solutions also produces overeating, overweight, and obesity (Sclafani and Xenakis, 1984 a, b). Indeed, feeding a polpsacchqide solution might be a better method of producing obesity than feeding sugar in any form since the ratio of adiposity in rats given polysaccharide solution to

10 I. RAMIREZ

adiposity in control rats was 2.9 (Sclafani & Xenakis, 1984 b), greater than that obtained in any other report in this review (see above for method of computation and other values). This finding suggested to the reviewer that obesity might be produced by any nutritive solution regardless of its sugar content.

HEREDITARY OBESITY AND SUCROSE FEEDING

Nutritional Method

It would be of interest to know the effects of hereditary susceptibility to obesity on response to sucrose feeding. Using the nutritional method, Winand and Christophe (1977) found that both normal and ob/ob mice gained less weight and became less fat when fed sugar-based diets compared to a starch based diet. On the other hand, Michaelis et al. (1983, 1984) found that sucrose feeding increased body weight and fat pad weight but not food intake in both normal and cp/cp rats. Michaelis et al. (1980) found that sucrose content of the diet had little or no effect on food intake, body weight and adiposity of ad libitum fed Zucker Fatty and lean rats. However, both genotypes showed bigger sucrose effects when they were meal fed. Both Zucker Fatty and lean rats responded to sucrose in a qualitatively similar way (Michaelis et al., 1980).

Solution Method

Studies using the solution method are equally inconsistent. Ramirez and Sprott found that yellow obese mice (1979) and ob/ob mice (1978) usually regulated caloric intake as well as or better than normal mice when given sucrose or glucose solutions to drink. The one exception was that young yellow mice (6-7 weeks of age) increased caloric intake more than did normal mice of the same age when given sucrose solutions to drink (Ramirez & Sprott, 1979). On the other hand, Flier et al. (1981) reported that whereas normal mice increased caloric intake by 27%, ob/ob mice increased caloric intake by 80% when given sucrose solution to drink; the age of the animals was described as 6 to 12 weeks of age. Zucker Fatty rats appear to regulate caloric intake as well as or better than lean rats when given a sucrose solution to drink (Castonguay et al., 1985). All the above studies used obese mutants. One study compared two unrelated strains of rats, one susceptible to high-fat diet induced obesity and one resistant. As might be expected, the susceptible strain (Osborne-Mendel) increased body weight and fat when given sucrose, whereas the resistant strain (S 5B/Pl) did not (Schemmel etal., 1982). Overall, there does not seem to be any clear relationship between hereditary obesity and susceptibility to sucrose-induced obesity.

MECHANISM OF ACTION: PREVIOUS SPECULATIONS

Very little attention has been given to understanding the mechanisms by which sugars alter appetite, weight gain and obesity. This section briefly summarizes some possibilities. Fullerton et al. (1985), Geiselman and Novin (1982) and Kanarek and Hirsch (1977) have discussed possible mechanisms in more detail.

The most obvious explanation for overconsumption of sweet foods is that rodents find sweet foods highly palatable. It is difficult to find much data supporting or

SUCROSE 11

contradicting this notion. There does not seem to be a linear correlation between the sweetness of a sugar and its effects on appetite or obesity (see earlier). Adding saccharin to glucose solutions increases glucose intake but does not increase total caloric intake (Smith & Foster, 1980). The only evidence suggesting that sweet taste may play a role is that adding saccharin to a polysaccharide solution increased calorie intake and weight gain, although this effect was not significant (Sclafani & Xenakis, 1984).

Geiselman and Novin (1982) have suggested that consumption of sugar leads to hyperinsulinemia which in turn produces hypoglycemia which increases consumption of carbohydrate leading once again to hyperinsulinemia etc. These writers present a great deal of evidence consistent with this conjecture. The most serious difficulty with their idea is the lack of direct evidence for such a vicious cycle.

Fullerton et al. (1985) argued that interactions between sugar and brain neurotrans- mitters may be involved in sugar’s effects on obesity. At the present time, there are insufficient data to judge the validity of this hypothesis.

Almost no attention has been given_ to speculations about why sugars might decrease appetite. Harper and Spivey (1958) have suggested that the osmotic pressure exerted by sugars may modulate consumption of diets containing sugars. They present data indicating an inverse correlation between the osmotic pressure that carbohydrates exert in solution and consumption of diets containing these carbohydrates in meal-fed rats. This idea could be extended to allow for differential rates of absorption of various sugars; those sugars which are absorbed slowly might exert greater osmotic effects in the intestinal tract but not in the stomach. For example, fructose is absorbed relatively slowly (Vrana 8z Fabry, 1983); this slow absorption might account for the reduced growth sometimes seen when it is the only carbohydrate in the diet (see above). Vasselli et al. (1982) have shown that slowing the absorption of sucrose pharmacologically blocks the obesity-inducing effects of a sucrose solution. This result might also be explained by the osmotic effects of unabsorbed sucrose in the gastrointestinal tract. The osmotic hypothesis, like the others, remains highly speculative.

MECHANISMSOF ACTION: ALTERNATIVE APPROACHES

Nutritional Method

Analyzing the mechanisms that operate in studies using the nutritional method will be difficult. One possible approach would be to consider the effects of sucrose on fat storage and oxidation. One theory of the regulation of food intake claims that oxidation of metabolic fuels inhibits food intake whereas storage of fuels in adipose tissue limits the availability of fuels for oxidation and hence stimulates food intake (Friedman & Stricker, 1976; Friedman & Ramirez, 1985). Sucrose feeding stimulates lipid synthesis by the liver (Back &Angel, 1982; Vrana & Fabry, 1983; Waterman et al., 1975) and hence might be expected to enhance fuel storage, thereby stimulating appetite. On the other hand, sucrose can reduce lipid synthesis in adipose tissue (Waterman et al., 1975) thereby decreasing adiposity and food intake. Whether sucrose increases or decreases appetite and adiposity may depend on the balance between these two opposing actions of sucrose. If this idea is correct, it would not be surprising that studies have produced inconsistent results.

The existence of a disaccharide effect supports the present hypothesis. Disac- charides that increase body weight and adiposity more than monosaccharides also increase levels of hepatic lipogenic enzymes (Michaelis & Szepesi, 1977; Michaelis et al.,

12 I. RAMIREZ

1978, 1980) without having any consistent effect on the levels of the same enzymes in adipose tissue (Michaelis et al., 1978). Meal feeding obliterated the disaccharide effect for liver lipogenic enzymes as well as for relative epididymal adipose tissue weight (Michaelis et al., 1980). That is, for meal-fed rats sucrose had the same effects as an equimolar mixture of glucose and fructose. Thus, changes in lipogenic enzymes might be correlated with changes in adipose tissue size.

The theoretical framework proposed here suggests that the best way to analyze the effects of sucrose on appetite is to examine the effects of sucrose on storage and oxidation of metabolic fuels. In my opinion this seems to be the most promising avenue for future research.

Solution Method

Presentation of sucrose solution alters several nutritional variables simultaneously (e.g. hydration of food, variety of foods available, intake of protein, fat, fiber, vitamins and minerals, etc.). It is very easy to control intake of essential nutrients by including them in the sucrose solution. This is equivalent to offering a liquid diet identical to the solid diet except that the liquid diet contains sucrose and water. Recent studies employing this approach have produced surprising results (Ramirez, 1986). Rats given a liquid diet containing sucrose in addition to a solid diet, consumed more calories than rats given a solid diet alone, regardless of the sucrose content of the solid diet. Prolonged feeding of the liquid diet increased total caloric intake and weight gain in comparison to feeding of the solid diet alone. Variety did not seem to be a major factor because rats given liquid diet alone consumed more calories and gained more weight than rats given only a solid diet. Most surprising of all, similar effects were seen when the liquid diet contained corn starch instead of sucrose. These findings suggest that overweight induced by sucrose solutions may be the result of offering rats a hydrated rather than a dry food source.

The notion that water rather than sucrose is the critical factor might seem difficult to accept since laboratory animals are commonly given plain drinking water ad libitum. However, two lines of evidence support this hypothesis. Adding water to sucrose results in increased intake of sucrose (Kanarek & Orthen-Gambill, 1982; Sclafani & Kramer, 1983) and decreased efficiency of weight gain (Kanarek & Orthen-Gambill, 1982). Secondly, adding water to rat diets can increase caloric intake and weight gain (e.g. Adkins et al., 1967; Bernardis & Bellinger, 1982; Keane, Smutko, Krieger & Denton, 1962,1963) and even adiposity (Adkins et al., 1967). Adding water to a low protein diet can improve efficiency of protein utilization even when the rats fed wet diets are pair fed to rats fed a dry diet (Keane et al., 1963). Most studies of wet foods employed diets containing little or no sugar. Human beings commonly add water to grains before consuming them; these same grains are fed to rats in dry form in their stock diets. It is conceivable that adding water to a food before it is consumed alters the palatability or digestion of the food. It is even possible that adding water to foods alters the way they are digested, stored or oxidized. This subject deserves more attention.

RELEVANCE TO HUMANS

One of the primary reasons for conducting the research cited above was to gain insight into how sucrose might affect humans. Just how this insight can be applied,

SUCROSE 13

however, is rarely addressed. It is not appropriate to simply assume that humans will respond to diets in the same way as animals. In the author’s opinion, it is possible to make inferences about humans from animal data if two preconditions can be satisfied: (1) the situations in which the phenomena occurs in animals also occur in humans, and (2) the physiological mechanisms involved are similar in animals and humans. The first precondition requires one to have a good understanding of the conditions necessary for sucrose to increase adiposity and appetite. This precondition is not satisfied since it is unclear why sucrose does not affect appetite and adiposity in a consistent manner. The second precondition requires one to demonstrate which physiological and biochemical processes are involved in sucrose’s effects on appetite and adiposity, and whether the same processes can occur in humans. At present, our knowledge about mechanisms consists largely of speculation. Thus, there is no justification, at present, for applying results from animal studies to humans.

There are reasons, however, to think that animal studies may not be directly applicable to humans. First of all, most studies involved very large changes in the sugar content of the diet, typically 5@65°~ sucrose vs. a sugar-free diet. In contrast, humans in wealthier countries consume roughly l&24% of their calories as sucrose, and in poorer countries sucrose is an even less important nutrient (Anderson, 1982). Studies using the solution method almost invariably involve comparisons between rats given a single dry food and rats given the dry food and sugar solution. Humans, on the other hand, usually eat a wide variety of foods. Kratz and Levitsky (1979) reported that rats given a variety of foods to chose from did not appear to overeat or gain excess body weight when given solid sucrose whereas rats given sucrose plus a single food did overeat and gained excess body weight. It was pointed out above that the growth promoting effects of sucrose solutions may be due to presentation of a wet food source rather than to sucrose per se. Human foods, unlike laboratory rat diets, usually contain substantial amounts of water.

None of the above proves that sucrose cannot produce obesity in humans or that animal studies cannot help resolve this issue. Rather, better animal studies are needed. Animal studies have demonstrated that different carbohydrates can have very different effects on food intake, body weight and adiposity. Indeed, the only convincing evidence for this comes from animals.

CONCLUSIONS

Nutritional us Solution Method

Feeding sucrose to rats and mice often, but not always, increases their food intake, body weight and adiposity. One factor accounting for variable results is the method of feeding sucrose. For adult animals, replacing the starch in the diet with sucrose (nutritional method) has milder and less reliable effects than does offering the sucrose as a solution along with dry solid food (solution method). On the other hand, it is difficult to produce obesity in weanling rats with the solution method, whereas it has been frequently produced in weanling rats with the nutritional method. For the nutritional method, feeding low protein diets can block or even reverse sucrose’s obesity-inducing effects. For the solution method, offering sucrose can produce overeating even when

14 I. RAMIREZ

low levels of protein are consumed. Meal feeding accentuates sucrose’s obesity inducing effects in studies employing the nutritional method. Giving sucrose solution to meal-fed rats can lead to reduced food intake and weight loss. The fat content of the diet has little effect on the results obtained with the nutritional method but has major effects on the results obtained with the solution method. Studies employing the nutritional method generally find that replacing sucrose with another sugar alters the results obtained; disaccharides often have greater effects than monosaccharides. Studies employing the solution method usually find similar results with different sugars; monosaccharides seem to be just as effective as the disaccharide sucrose.

It is probable that entirely different mechanisms are Involved in the two kinds of studies. For the solution method, one critical factor seems to be presentation of a hydrated source of calories in addition to dry food, rather than to sucrose per se. Presumably, wet foods are more palatable or digested differently than dry foods. Other factors, such as altered intake of essential nutrients, might also play a role. There is no evidence that the type of carbohydrate used in the solution has any effect on the results obtained. For studies employing the nutritional method, sucrose’s effects on lipogenesis and fat storage may mediate its effects on obesity. Until more is known about mechanisms, animal data cannot be used to make inferences about whether sucrose is a causative agent in human obesity.

~elatio~s~~p between Appetite and Adiposity

Studies employing the nutritional method usually indicate that feeding sucrose increases the efficiency of weight gain. Thus, animals fed sucrose by the nutritional method tend to become fatter than would be expected on the basis of their caloric intake. Studies employing the solution method often give the reverse result. Rats given sucrose solutions to drink in addition to their usual food tend to become less obese than would be expected from the elevated food intake. It is of interest that feeding granular sucrose in addition to the usual food can result in increased feed efficiency.

Confidence in these conclusions is weakened by two factors. First, the literature is inconsistent, contrary exahples may be found for each conclusion. Second, most studies used an inadequate measure of efficiency of weight gain; the ratio of weight gained divided by calories consumed. More precise methods (e.g. Rothwell & Stock, 1984) should be applied in future studies.

Does Sucrose cause Obesity?

Inconsistencies in the literature make it difficult to reach definite conclusions about the relationship between sucrose feeding and appetite and adiposity. Different investigators conducting superficially similar experiments often fail to obtain similar results. Studies with hereditary obesity have been particularly inconsistent. Strain differences are probably one factor responsible for discrepant results. Such inconsistencies are a severe constraint on anyone arguing that sucrose is a major contributor to human obesity.

In conclusion, feeding rodents very large amounts of sucrose occasionally increases caloric intake sometimes causes mild obesity. Animal data provide no support for the idea that sucrose consumption is a major factor in the development of human obesity.

SUCROSE 15

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Received 28 February 1986, revision 29 July 1986

When does sucrose increase appetite and adiposity?

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