Soy, Phytoestrogens and Metabolism A Review (Volume) Molecular and Cellular Endocrinology (Issue)

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MCE 7153 1–13 ARTICLE IN PRESS

Molecular and Cellular Endocrinology xxx (2009) xxx–xxx
Contents lists available at ScienceDirect
Molecular and Cellular Endocrinology

journal homepage: www.elsevier.com/locate/mce
1 Review
2 Soy, phytoestrogens and metabolism: A review

3 Christopher R. Cederroth, Serge Nef ∗
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4 Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva 4, Switzerland
5
6 a r t i c l e i n f o a b s t r a c t
7
8 Article history: Of any plant, soy contains the largest concentration of isoflavones, a class of phytoestrogens. Phytoestro-
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9 Received 14 January 2009 gens are structurally similar to estradiol and mimic its effects. Soy and phytoestrogens receive increasing
10 Accepted 24 February 2009 attention due to the health benefits associated with their consumption. Here we review the data collected
11 on the effects of soy and phytoestrogens on glucose and lipid metabolism and their possible mechanisms
12 Keywords: of action. Overall, there is a suggestive body of evidence that soy and dietary phytoestrogens favorably
13 Dietary soy
alter glycemic control, improve weight and fat loss, lower triglycerides, low density lipoprotein (LDL)
14 Phytoestrogens
cholesterol and total cholesterol. However, these results must be interpreted with care, and additional
15 Isoflavones
evidence is needed before a firm conclusion can be drawn. In particular, since not all activities related
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16 Genistein
17 Endocrine disruptor to soy can be assigned to the estrogenic-like activity, further studies are needed to identify firstly which
18 Obesity soy constituent(s) improve metabolic parameters when ingested and secondly, which are the mecha-
19 Glycemia nisms whereby dietary soy improves metabolic-related conditions like obesity and diabetes. Finally, the
potential detrimental effects of soy and phytoestrogens are briefly discussed.
© 2009 Published by Elsevier Ireland Ltd.
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20 Contents
21 1. Metabolic diseases and therapeutic alternatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

22 2. Soybean composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
23 3. Absorption and metabolism of isoflavones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
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24 4. Soy consumption and phytoestrogen levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

25 5. Phytoestrogens: complex hormetic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
26 6. Role of estrogens in metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
27 7. Effects of soy protein and phytoestrogens on human metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
28 8. Actions of soy on metabolism in rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
29 9. Central actions of phytoestrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
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30 10. Potentially adverse effects in consuming soy and soy-derived phytoestrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

31 11. Summary and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
32 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
33 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
34
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35 1. Metabolic diseases and therapeutic alternatives to surpass malnutrition and infectious diseases as the most sig- 43
nificant contributor to worldwide morbidity. In western societies, 44

36 Obesity and its related disorders, such as type 2 diabetes, car- for the first time in modern history, life expectancy of newborns is 45
37 diovascular diseases (CVD), high blood pressure, dyslipidemia [high declining as a result of these metabolic disorders (Olshansky et al., 46
38 levels of circulating triacylglycerols and low density lipoprotein 2005). The rapid increase in obesity suggests that life-style factors 47
39 (LDL) cholesterol, and low levels of high density lipoprotein (HDL) such as high-calorie diets, physical inactivity and potentially envi- 48
40 cholesterol], have recently become a major health problem reaching ronmental endocrine disruption, rather than genetics, are the most
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49
41 pandemic proportions (Engelgau et al., 2004). These diseases, com- plausible causes. 50
42 monly referred to as the Metabolic Syndrome (MS), are beginning Although the source of metabolic disorders is often the diet 51
itself, nutrition can also form part of the solution, in fact provid- 52
ing health benefits. Usually dietary intervention to control excess 53
∗ Corresponding author. body weight, hyperglycemia and dyslipidemia has included low 54
E-mail address: Serge.Nef@medecine.unige.ch (S. Nef). energy and low fat diets, but these are of limited efficacy due to 55
0303-7207/$ – see front matter © 2009 Published by Elsevier Ireland Ltd.

doi:10.1016/j.mce.2009.02.027
Please cite this article in press as: Cederroth, C.R., Nef, S., Soy, phytoestrogens and metabolism: A review. Mol. Cell. Endocrinol. (2009),
doi:10.1016/j.mce.2009.02.027
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2 C.R. Cederroth, S. Nef / Molecular and Cellular Endocrinology xxx (2009) xxx–xxx
56 the strict and long-term commitment required. However, long term 2. Soybean composition 121
57 health benefits can be gained from dietary proteins and bioac-

58 tive non-nutrients, called phytochemicals, which could be either Soybean (Glycine max) is composed of macronutriments such 122
59 incorporated into the diet or be part of the food itself. These phyto- as lipids, carbohydrates and proteins. Soybean lipids, which are 123
60 chemicals are biologically active plant-derived compounds, which deprived of cholesterol, contain about 15% of saturated fat, 61% of 124
61 structurally and functionally mimic estrogens (Dixon, 2004). Phy- polyunsaturated fat, and 24% of monounsaturated fat (USDA, 1979). 125
62 toestrogens are found in numerous fruits and vegetables and are Carbohydrates make up about 30% of the seed, with 15% being solu- 126
63 categorized into three classes, namely the isoflavones, lignans and ble carbohydrates (sucrose, raffinose, stachyose) and 15% insoluble 127
64 coumestans. While phytoestrogens are ubiquitous within the plant carbohydrates (dietary fiber). The protein content of soybean varies 128
65 kingdom, isoflavones are mainly found in the soybean—the most from 36% to 46% depending on the variety (Garcia et al., 1997; 129
66 important dietary source of phytoestrogens for humans, cattle and Grieshop and Fahey, 2001; Grieshop et al., 2003). Storage proteins 130
67 rodents. Isoflavones have a non-steroidal structure but possess a are predominant, such as the 7S globulin (␤-conglycinin) and 11S 131
68 phenolic ring that enables them to bind the estrogen receptor (ER) globulin (glycinin), which represent about 80% of total protein con- 132
69 and act either as estrogen agonists or antagonists (Makela et al., tent, as well as less abundant storage proteins such as 2S, 9S, and 133
70 1994, 1995). 15S globulins (Garcia et al., 1997). Interestingly, ␤-conglycinin but 134
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71 The fact that isoflavones have been shown to exert estrogenic not glycinin is capable of improving serum lipid profiles in mice and 135
72 effects raises the possibility that this class of phytochemicals humans, in the absence of phytoestrogens (Moriyama et al., 2004; 136
73 may affect glucose and lipid metabolism. In fact, estradiol itself Kohno et al., 2006). 137
74 is a well known modulator of glucose homeostasis, which also Soybean also contains micronutriments, which include 138
75 affects obesity development. For instance, postmenopausal women isoflavones, phytate, soyaponins, phytosterol, vitamins and 139
develop visceral obesity and insulin resistance and are at an minerals. Although beneficial effects of micronutriments such as
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76 140
77 increased risk of diabetes but estrogen replacement therapy nor- saponins and phytosterols on cholesterol levels and absorption 141
78 malizes these abnormalities (Ahmed-Sorour and Bailey, 1980; have been reported (Oakenfull, 2001; Lukaczer et al., 2006), there 142
79 Bailey and Ahmed-Sorour, 1980; Gambacciani et al., 1997). From is an increasing body of literature suggesting that isoflavones may 143
80 genetic studies in rodents, it has been shown that these effects additionally have a beneficial role in lipid and glucose metabolism. 144
81 are mediated by estrogen receptors (see below). This has caused Soybeans are the most abundant source of isoflavones in food. 145
82 researchers to focus on the identification of Selective Estro- Studies have shown that there is a large variability in isoflavone 146
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83 gen Receptor Modulators (SERMs) that could be of potential content and composition in soybeans. This is function of the 147
84 therapeutic interest for the treatment of metabolic disorders, variety of soy grown, as well as environmental conditions (Wang 148
85 without having negative effects. Studies in humans and rodents and Murphy, 1994; Caldwell et al., 2005). Abiotic and biotic stresses 149
86 support the hypothesis that soy proteins or soy-derived phytoe- such as variation in temperature, drought or nutritional status, 150
87 strogens may be beneficial for the prevention of obesity and pest attack or light conditions may modify isoflavone content 151
88 diabetes (Bhathena and Velasquez, 2002; Velasquez and Bhathena, and composition. As a consequence, total isoflavone content may 152
89 2007). vary up to 3-fold with growth of the same soy cultivar in different 153
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90 The complex interactions between soy proteins and isoflavones geographical areas and years (Wang and Murphy, 1994). 154
91 are fairly well understood. To understand these intricate relation-

92 ships, one must assess the biological activity of soy components,
3. Absorption and metabolism of isoflavones 155
93 both in isolation and in combination. So far, few studies have
94 shown that pure soy-proteins or soy proteins isolate (SPI) alone
The metabolism of isoflavones is rather complex. The two major
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156
95 (in absence of isoflavones) can provide beneficial metabolic effects
isoflavones, genistein and daidzein, are present in soy as ␤-D- 157
96 (Velasquez and Bhathena, 2007). The majority of the studies using
glycosides, namely genistin and daizin (Fig. 1). These glycoside 158
97 SPI remain difficult to interpret because of the lack of clarity con-
forms are biologically inactive (Setchell, 1998). Once ingested, 159
98 cerning the presence or absence of isoflavones in the diet. On
isoflavone glycosides are hydrolyzed by bacterial ␤-glucosidases 160
99 the other hand, soy-derived phytoestrogens have received more
in the intestinal wall, resulting in the conversion to their corre- 161
100 attention mainly due to their benefits in decreasing age related
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sponding bioactive aglycones (genistein and daidzein). Only the 162

101 diseases (e.g. osteoporosis, cardiovascular disease), or hormono-
aglycone forms are absorbed by the intestinal tract and are there- 163
102 dependent cancers (e.g. prostate) (Setchell, 1998; Tham et al.,
fore biologically active. Daidzein can be further metabolized to 164
103 1998; Sacks et al., 2006). Concerning metabolism, the American
equol and O-demethyangolensin, and genistein to p-ethyl phenol. 165
104 Food and Drug Administration (FDA) authorized in 1999 the label-
In fact, genistein, daidzein, equol and O-demethyangolensin are the 166
105 ing of health claims on food containing soy proteins, referring to
major isoflavones detected in the blood and urine of humans and 167
106 the beneficial role of soy protein in reducing the risk of coro-
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animals (Setchell, 1998). In rodents, equol is the major circulat- 168

107 nary heart disease (CHD). The beneficial effects on metabolism
ing metabolite among isoflavones representing up to 70–90% of 169
108 in humans have been hotly debated, but studies in rodents may
all circulating isoflavones. While all rodents are equol producers, 170
109 help in identifying the biologically relevant soy components and
only 30% of humans are able to metabolize daidzein into equol 171
110 the intimate mechanisms involved. The purpose of this review is
(Atkinson et al., 2005). It remains unclear whether the effectiveness 172
111 to examine the evidence regarding the use of soy and phytoestro-
of dietary phytoestrogens in reducing the risks of obesity, diabetes, 173
112 gens in the prevention of obesity and diabetes mellitus in animals
and cardiovascular disease in humans correlates with the ability of
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174
113 and humans. We also discuss the mechanisms by which soy and
individuals to metabolize daidzein into equol. However, it is a likely 175
114 dietary phytoestrogens may affect glucose and lipid metabolism
source of variability and therefore should be taken into account 176
115 and improve the control of body weight and glucose homeosta-
when performing clinical trials with soy or dietary phytoestrogens. 177
116 sis. To provide context and the requisite background information,
117 we begin with a brief overview about soybeans, the nutritional
118 composition of soy. We also present scientific evidence both in 4. Soy consumption and phytoestrogen levels 178
119 humans and rodents supporting or refuting the potential ben-

120 eficial effects of soy and phytoestrogens on glucose and lipid In soybean, isoflavones are tightly associated with proteins. 179
metabolism. As mentioned, the abundance of isoflavones varies according 180
doi:10.1016/j.mce.2009.02.027
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C.R. Cederroth, S. Nef / Molecular and Cellular Endocrinology xxx (2009) xxx–xxx 3
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Fig. 1. The molecular structure of isoflavones resembles that of 17␤-estradiol. Isoflavones are found in vegetables and fruits in a biologically inactive glycoside form (genistin,
daidzin and glycitin). After ingestion, ␤-glucosidases from the intestine cleave the glucosyl residue and generate biologically active aglycones (genistein, daidzein and glycitein).
Daidzein can be further metabolized into equol.
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181 to soy variety and culture conditions, but is also dependent dose, intestinal transit time and the chemical composition of the 212
182 on the way soybeans have been processed. Indeed, isoflavones dietary isoflavones. 213
183 can be dissociated from soy-proteins using alcohol extraction

184 which significantly diminishes the amount of bound-isoflavones
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185 (Bhathena and Velasquez, 2002). This explains the substantial vari- 5. Phytoestrogens: complex hormetic compounds 214
186 ability of phytoestrogen content found in soy products [0.1–5 mg

187 isoflavones/g of soy protein in mature and roasted soybeans, In plants, the synthesis of phytoestrogens, such as soy 215
188 0.3 mg/g soy protein in green soybeans and tempeh, 0.1–2 mg/g isoflavones, generally coincides with environmental stresses such 216
189 soy protein in tofu and some soy milk preparations (Bhathena and as pest infection, drought or lack of nutrients (Howitz and Sinclair, 217
190 Velasquez, 2002)]. 2008). Recently it has been suggested that stress-induced plant 218
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191 Numerous studies have included the investigation of the plasma compounds upregulate stress resistance pathways in animals. This 219
192 concentration of phytoestrogens and their metabolites in humans phenomenon, called xenohormesis, proposes that chemical clues 220
193 and animals consuming a diet with or without soy (Adlercreutz from autotrophs (e.g. plants) provide an advance warning about 221
194 et al., 1993a; Morton et al., 1994; Coward et al., 1996). In humans the deterioration of the environment, allowing heterotrophs (e.g. 222
195 consuming soy-free diets, plasma concentration of isoflavones is mammals) to mount a preemptive defense response while condi- 223
196 usually in the nanomolar range ≤40 nM (Morton et al., 1994; van tions are still favorable (Howitz and Sinclair, 2008). This theory has 224
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197 Erp-Baart et al., 2003). In contrast, acute ingestion of dietary soy been recently adopted to explain the health benefits provided by 225
198 leads to a rapid increase in the plasma concentration of isoflavones stress-induced phytochemicals such as polyphenols, a group which 226
199 up to the micromolar range (Adlercreutz et al., 1993b; Xu et al., includes stilbenes (e.g. resveratrol found in red wine and peanuts), 227
200 1994; King and Bursill, 1998; Watanabe et al., 1998). Pharmacoki- catechins (e.g. epigallocatechin-3-gallate or EGCG found in green 228
201 netic studies confirm that healthy adults absorb isoflavones rapidly tea), anthocyanidins, and most relevant to this review, isoflavones. 229
202 and efficiently (Setchell et al., 2001). The fates of daidzein, genis- Similarly, we believe that the isoflavones genistein and daidzein 230
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203 tein and their respective ␤-glycosides are similar. The average time mediate most of their biological effects through the modulation of 231
204 taken after ingesting the aglycones to reach peak plasma concentra- key mammalian enzymes and receptors of stress-response path- 232
205 tions is 4–7 h, which is delayed to 8–11 hours for the corresponding ways or estrogen-dependent pathways, rather than through their 233
206 ␤-glycosides. This suggests that the rate-limiting step for absorp- well known antioxidant (Vedavanam et al., 1999) or tyrosine kinase 234
207 tion is the initial hydrolysis of the glycosidic moiety. The half-life inhibitory properties (Akiyama et al., 1987). The affinity of phy- 235
208 for daidzein and genistein was reported to be 9.3 and 7.1 h respec- toestrogens for estrogen receptors results in effects on a large 236
209 tively, indicating that isoflavones or their metabolites are rapidly number of estrogen-regulated systems, including the cardiovascu- 237
210 excreted. Finally, factors that might influence isoflavone bioavail- lar, metabolic, reproductive, skeletal and central nervous systems. 238
211 ability include intestinal microflora, food matrix, the administered A significant characteristic of isoflavones is their capacity to bind 239
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Table 1
Q3 Relative binding affinity (RBA) and relative transactivation activity (RTA) of various estrogenic compounds, isoflavones and endocrine disruptors in comparison with 17␤-
estradiol.
Compound Relative binding affinity Relative transactivation
ER␣ ER␤ ER␣ ER␤
17␤-estradiol 100 100 100 100

Diethylstilbestrol (DES) 236 221 117 69
Tamoxifen 4 3 6 2
Coumestrol 20 140 102 98
Isoflavones Genistein 4 87 198 182

Daidzein 0.1 0.5 97 80
Formononetin <0.01 <0.01 6 2
Biochanin A <0.01 <0.01 36 53
Ipriflavone <0.01 <0.01 11 3
Endocrine disruptors Bisphenol A 0.01 0.01 50 41
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o,p -DDT 0.01 0.02 54 10
Nonylphenol 0.05 0.09 62 34
Methoxychlor <0.01 <0.01 9 2
The RBA of each competitor was calculated as the E2:competitor concentration ratio required to reduce the specific radioligand binding by 50% (ratio of IC50 values). The RBA
value for E2 was arbitrarily set at 100. The RTA of each compound was calculated as the ratio of the luciferase reporter gene induction value, at a concentration of 1 ␮M of
the relevant compound, relative to the luciferase reporter gene induction value using 17␤ estradiol at 1 ␮M. The transactivation activity of 17␤ estradiol was arbitrarily set at
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100. Data adapted from Kuiper et al. (1998).
240 both to estrogen receptors (ERs) ␣ and ␤ (Kuiper et al., 1997, 1998), is associated with a decreased expression of genes responsible 280
241 with preferential binding of genistein to ER␤ (Table 1). Specific for fatty acid oxidation, but can be normalized with E2 treatment 281
242 binding affinity to ERs enables isoflavones to elicit both estrogenic (Nemoto et al., 2000). The function of ER␤ is less clear—to date no 282
243 and antiestrogenic effects depending on the tissue, as well as on overt metabolic phenotype has been described in mice lacking this 283
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244 isoflavone and endogenous estradiol levels. For instance, in var- receptor (␤ERKO), under normal dietary conditions (Ohlsson et al., 284
245 ious cell lines, in the presence of physiological levels (1 nM) of 2000). Recently, it was found that, when challenged with a high fat 285
246 estradiol (E2), genistein acts as an anti-estrogen whereas at lev- diet, ␤ERKO mice increase their weight and adiposiy to a greater 286
247 els of E2 found in postmenopausal women (0.01 nM), genistein extend than do wild-type mice (Foryst-Ludwig et al., 2008). 287
248 shows additive agonistic effects (Hwang et al., 2006). Genistein Estrogens have also been shown to modulate glucose 288
249 also has ER-mediated biphasic effects in intestinal cell prolifera- metabolism in rodents. For instance in models of type 2 diabetes, 289
250 tion (Chen and Donovan, 2004). Thus, isoflavones, as stress-induced ovariectomy induces hyperglycemia, whereas in males, estrogen 290
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251 phytochemicals, may provide health benefits through their selec- perfusion reverses diabetes (Louet et al., 2004). Similarly, mice lack- 291
252 tive estrogen receptor modulator (SERM) activities. ing either functional ER␣ or aromatase display glucose intolerance 292
and insulin resistance (Heine et al., 2000; Jones et al., 2000; Takeda 293
et al., 2003). Indeed, ER␣ and ER␤ are both expressed in muscle 294
253 6. Role of estrogens in metabolism cells and are known to modulate the expression of the glucose 295
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transporter 4 (Glut4), a key molecule for the import of glucose in 296
254 Studies in humans and rodents have shown that ERs are impor- cells (Barros et al., 2006). The endocrine pancreatic function is also 297
255 tant mediators of the action of estrogen on lipid and glucose directly modulated by estrogen levels. In rats, circulating insulin 298
256 metabolism. Estrogens have been reported to affect adiposity either levels have been shown to vary during the estrous cycle (Bailey 299
257 directly, by modulating lipogenesis, lipolysis or adipogenesis, or and Matty, 1972). Estrogens and endocrine disruptors such as 300
258 indirectly, by modulating appetite or energy expenditure (Cooke Bisphenol-A (BPA) have been reported to modulate insulin content 301
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259 and Naaz, 2004). As mentioned above, the concept of estrogens in ␤-cells via ER␣, but not via ER␤ (Alonso-Magdalena et al., 2008). 302
260 modulating metabolic features derived originally from the obser- These molecules also protect ␤-cells from oxidative stress, apopto- 303
261 vation that postmenopausal women develop visceral obesity and sis, and streptozotocin-induced injuries in both genders, through 304
262 insulin resistance as a result of low levels of estrogens. Interest- ER␣ (Le May et al., 2006). In addition, several studies reported that 305
263 ingly, hormonal replacement therapy normalizes these symptoms estrogens increase glucose-stimulated insulin secretion in isolated 306
264 (Ahmed-Sorour and Bailey, 1980; Bailey and Ahmed-Sorour, 1980). islets (Nadal et al., 1998; Adachi et al., 2005; Alonso-Magdalena et 307
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265 Estrogens also play an important role in glucose homeostasis, and al., 2006, 2008; Le May et al., 2006; Martensson et al., 2008). 308
266 are known to modulate insulin sensitivity (Godsland, 2005). Vari- Finally, estrogens have been reported to modulate energy home- 309
267 ations in human glucose homeostasis are observed during the ostasis indirectly, through the central nervous system (CNS) and 310
268 menstrual cycle, and diabetes becomes more resistant to treatment the hypothalamus. By sensing endocrine and metabolic signals, the 311
269 during the luteal phase (Case and Reid, 2001). Relevant genetic hypothalamus engages distinct effector pathways, which result in 312
270 evidence that estrogen modifies metabolism can also be found behavioral, endocrine and metabolic changes, to maintain energy 313
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271 in humans: individuals with mutations in the aromatase gene, an homeostasis. Several hormones are capable of influencing energy 314
272 enzyme that converts androgens into estrogens, display truncal intake and expenditure. For instance, leptin and insulin modulate 315
273 obesity, insulin resistance and hyperlipidemia (Carani et al., 1997). the activity of hypothalamic neurons in the arcuate nucleus, ulti- 316
274 Studies in rodents are far more advanced, and confirm the impor- mately leading to changes in food intake (Schwartz et al., 2000). It 317
275 tance of ER␣ in modulating both lipid and glucose metabolism. Mice has been shown recently that estrogens are among the hormones 318
276 lacking either ER␣ or the aromatase gene have increased adipos- that modulate the energy balance. Deficiency in aromatase or ER␣, 319
277 ity and fatty livers (Heine et al., 2000; Jones et al., 2000; Takeda or ovariectomy, decreases physical activity and energy expendi- 320
278 et al., 2003), confirming the role of estrogens in the regulation ture (Heine et al., 2000; Cooke et al., 2001; Meli et al., 2004), 321
279 of adiposity. In aromatase knockout mice (ArKO), liver steatosis whereas treatment with E2 increases locomotor activity through 322
doi:10.1016/j.mce.2009.02.027
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323 an ER␣-dependent mechanism (Ogawa et al., 2003). Both estro- with soy protein isolates for 12 weeks had lower body weight and 369
324 gen receptors are found in the hypothalamic nuclei and modulate BMI, with decreased cholesterol and LDL levels in the blood (Allison 370
325 food intake (Liang et al., 2002) and locomotor activity (Ogawa et et al., 2003). Additionally, a 6-month clinical trial was conducted 371
326 al., 2003). Specific silencing of ER␣ in the hypothalamus of female to compare the effects of isoflavones with that of conjugated estro- 372
327 rodents leads to similar phenotypes to those observed in consti- gens on blood glucose, insulin, and lipid profiles in postmenopausal 373
328 tutive mutant mice, including obesity, hyperphagia and reduced Taiwanese women. The study revealed that during fasting both glu- 374
329 energy expenditure (Musatov et al., 2007). Although it remains cose and insulin levels were significantly reduced by soy isoflavones 375
330 unknown whether or not these phenotypes are associated with (100 mg/day) and conjugated estrogens (0.625 mg/day) (Cheng et 376
331 changes in the expression of hypothalamic neuropeptides, these al., 2004). 377
332 results show that hypothalamic ER␣ is essential in the regulation of In contrast to the above mentioned trials, a significant number 378
333 energy balance. Supporting a direct effect of E2 on the hypothalamic of studies reported an absence of beneficial effects of soy on classi- 379
334 control of adiposity, it was shown that E2 modulates hypothalamic cal metabolic parameters such as body weight, serum lipid profiles, 380
335 synapticity by bypassing the leptin receptor to act directly on the fat mass, blood glucose and insulin profiles (Yamashita et al., 1998; 381
336 downstream Stat3 signaling in the hypothalamus, thus decreasing Anderson and Hoie, 2005; Li et al., 2005; Hall et al., 2006; Ikeda 382
337 body weight (Gao et al., 2007). et al., 2006; Anderson et al., 2007). These discrepancies make it 383
OF
338 Overall, estrogens appear to be crucial regulators of metabolic difficult to draw firm conclusions regarding the beneficial effect 384
339 functions by directly and indirectly (via the CNS) modulating energy of soy on glucose and lipid metabolism. When comparing these 385
340 homeostasis. Whether or not dietary soy and phytoestrogens have different clinical trials, the underlying causes of conflicting results 386
341 effects on energy homeostasis through estrogen-mimics is still a are probably related to the variability of experimental designs and 387
342 matter of controversial debate, but is clearly a plausible hypothesis. exposition protocols (route of administration, composition, dose, 388
and duration), the capacity of individuals to produce equol and
RO
389
the genetic susceptibility. Clearly more standardized studies are 390

343 7. Effects of soy protein and phytoestrogens on human needed to further evaluate these putative beneficial effects. 391
344 metabolism
345 The low frequency of obesity and related metabolic disorders 8. Actions of soy on metabolism in rodents 392
346 in Asian populations has drawn attention towards soy, which is a

DP
347 characteristic component in asiatic diets. We searched the PubMed The current scientific evidence concerning the role of soy and 393
348 literature database for epidemiological and clinical studies evaluat- isoflavones in rodents is based on studies where animals have been 394
349 ing the effects of soy or isolated isoflavones on human metabolism, exposed either to purified isoflavones (injected or supplemented 395
350 and the main results are summarized in Tables 2–5. in the diet itself) or soy protein isolates (SPIs) (for a complete 396
351 Epidemiological studies have shown that type-2 diabetes is four list of studies, see Tables 6–10). The difficulty in analyzing SPI 397
352 times less prevalent in Japanese people in Tokyo than in Japanese- studies arises from the fact that information on isoflavone levels 398
353 Americans in Seattle (Fujimoto et al., 1987, 1991). Consumption of and composition are quite often incomplete, making interpreta- 399
TE
354 more than 12.6 grams of soy protein per day is associated with a tions problematic and comparisons hazardous. On the other hand, 400
355 lower risk of glycosuria, a strong predictor of diabetes (Yang et al., supplementation of the diet with soy proteins is more relevant 401
356 2004). Similarly, several studies have reported that isoflavone con- than injection-based studies. This does, however, raise questions 402
357 sumption by postmenopausal women correlated with lower body as to which compound is responsible for the observed effects and 403
358 mass index (BMI), and higher HDL levels (Guthrie et al., 2000; whether the relative benefits of soy are not in fact due to the poor 404
EC
359 Goodman-Gruen and Kritz-Silverstein, 2001, 2003). performance of casein itself, which is usually used as control pro- 405
360 Clinical studies also suggest that soy protein or isoflavones may tein. 406
361 improve metabolic parameters. For instance, a metaanalysis of 38 In comparison to human studies which mainly focus on serum 407
362 trials (Anderson et al., 1995) as well as more recent reports (Crouse lipid analysis because of the clinical importance of atherosclero- 408
363 et al., 1999; Takatsuka et al., 2000; Teixeira et al., 2000; Gardner et sis and the risk in cardiovascular diseases, reports in rodents are 409
364 al., 2001; Jayagopal et al., 2002; Greany et al., 2004) demonstrated rather oriented towards the assessment of soy-derived compounds 410
RR
365 a significant reduction in plasma concentrations of total and LDL on weight and fat loss, and in fewer cases, insulin sensitivity. Still 411
366 cholesterol in humans exposed to soy proteins. In addition, post- concerning the effects of soy or isoflavones on serum lipid profiles, 412
367 menopausal Japanese women treated for 24 weeks with isoflavones most rodent studies that have assessed these parameters under 413
368 exhibited a lower fat mass (Wu et al., 2006). Obese patients treated healthy or diabetic states point towards an improvement in total 414
Table 2
CO
Epidemiological studies evaluating the effects of soy or isoflavones on human metabolism.
Epidemiological studies evaluating the effects of soy or isoflavones on human metabolism
Model Number of Dose Metabolic Effects References

individuals (total)
Pre and postmenopausal women 323 Soy protein intake >12.61 g/day For >12.61 g/day: Lower risk in glycosuria in Yang et al. (2004)
postmenopausal women with BMI
UN
<25 kg/m2
Pre and postmenopausal women 944 Fermented soy bean No effects on W or F/BMI Ikeda et al. (2006)
Postmenopausal women 208 Genistein intake >1 mg/day No effects on G, I, TC, LDL, TG Goodman-Gruen and
Kritz-Silverstein (2001)
Lower F/BMI, increased HDL
Postmenopausal women 939 Isoflavone intake >0.236 mg/day No effects on F/BMI, TC, LDL, HDL, Lower TG de Kleijn et al. (2002)
In these studies, serum isoflavone levels were not evaluated. Abbreviations: W, weight; F/BMI, fat or body mass index; G, serum glucose; I, serum insulin; TC, total cholesterol;
LDL, low density lipoprotein; HDL, high density lipoprotein; TG, triglycerides; FFA, free fatty acids; ND, not determined. Parameters listed here that do not appear in the table
were not analyzed in the article in question.
doi:10.1016/j.mce.2009.02.027
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Table 3
Clinical studies performed using dietary supplementation with soy protein isolates (SPI).
Clinical Studies performed using dietary supplementation with soy protein isolates (SPI)
Model Number of Duration SPI and isoflavones intake Serum isoflavone Metabolic effects References
individuals
Young healthy normolipidemic Total = 22 13 days High isoflavone SPI Genistein: 0.75 No effects on TC, LDL, Sanders et al. (2002)
men and women (56 mg/day) vs low TG
isoflavone SPI (2 mg/day)
Daidzein: 0.3 Increased HDL
Equol: 0.1
Obese women 22 (21) 16 weeks SPI (15 g/day) ND No effects on W, Anderson et al. (2007)
(150 mg/day isoflavones) F/BMI, G, I, TC, LDL,
vs casein (15 g/day) HDL, TG
(10 mg/day isoflavones)
Postmenopausal women 100 (102) 12 months SPI (25.6 g/day) ND No effects on F/BMI Kok et al. (2005)
(99 mg/day isoflavones)
OF
vs milk
Moderate 31 (33) 12 weeks SPI with isoflavone ND No effects on W, Gardner et al. (2001)
hypercholesterolemic (80 mg) or without vs F/BMI, HDL, TG
postmenopausal women milk (42 g/day)
Lower TC, LDL
Moderate Total = 146 9 weeks SPI (25 g/day) (62 mg/day ND No effects on HDL, TG Crouse et al. (1999)
RO
hypercholesterolinemic men isoflavones) vs Casein
and women (25 g/day)
Lower TC, LDL
Normocholesterolinemic 71 (72) 6 weeks SPI with isoflavones ND No effects on W, Greany et al. (2004)
(44.3 mg/day) vs milk F/BMI, TC, LDL, HDL,
TG
Mildly hypercholesterolinemic 71 (72) 6 weeks SPI with isoflavones ND No effects on W, F/BMI Greany et al. (2004)
DP
(44.3 mg/day) vs milk
Lower TC, LDL, TG
Increased HDL
Obese men and women 50 (50) 12 weeks SPI vs control ND No effects on HDL Allison et al. (2003)
Lower W, BMI, TC, LDL
Overweight and obese men Total = 90 12 weeks SPI vs milk ND No effects on W, G, TC, Anderson and Hoie (2005)
and women LDL, HDL, TG
TE
Obese male and women 17 (19) 16 weeks SPI vs meat ND No effects on W, Yamashita et al. (1998)
F/BMI, G, TC, LDL, HDL,
TG
Obese men and women 46 (36) 3 or 6 months SPI vs individual dietary ND No effects on I, TC, Li et al. (2005)
intervention LDL, HDL, TG
Lower W, F/BMI, G
12 months SPI vs individual dietary ND No effects on W, Li et al. (2005)
EC
intervention F/BMI, G, I, TC, LDL,

HDL, TG
Abbreviations: SPI, soy protein isolate; W, weight; F/BMI, fat or body mass index; G, serum glucose; I, serum insulin; TC, total cholesterol; LDL, low density lipoprotein; HDL,
high density lipoprotein; TG, triglycerides; FFA, free fatty acids; ND, not determined. Parameters that do not appear in the table were not analyzed in the article in question.
Serum isoflavone values are expressed in ␮M. For control groups, the number of individuals (n) is shown in parentheses.
RR
415 cholesterol (TC) and/or triglyceride (TG) levels after consumption of days in C57/BL6 ovariectomized mice decrease adipose gain (Naaz 436
416 Q1 dietary soy, SPI, isoflavones or genistein (Kirk et al., 1998; Nasagawa et al., 2003). In contrast, in a study where male mice were exposed 437
417 et al., 2003; Ae Park et al., 2006; Penza et al., 2006; Cederroth et al., to daily oral doses of genistein of up to 50 mg/kg/day, fat mass was 438
418 2008; Nordentoft et al., 2008; Torre-Villalvazo et al., 2008). Only increased. However fat mass decreased at doses of 200 mg/kg/day 439
419 one study shows an absence of effects on total cholesterol and TG (Penza et al., 2006). Overall, these results suggest that high phar- 440
420 after consumption of SPI (Aoyama et al., 2000a,b). macological doses of phytoestrogens yielding serum levels in the 441
CO
421 As mentioned above, most studies have evaluated the effects micromolar range inhibit adipose tissue deposition. 442
422 of soy-derived compounds on adiposity. For instance, Long-Evans The mechanisms by which dietary soy and phytoestrogens 443
423 rats or ovariectomized (OVX) ddY mice fed with a soy-rich diet reduce adiposity are unclear. Recently it was found that increased 444
424 have reduced weight and less adipose deposition than those fed energy expenditure and locomotor activity coupled with a marked 445
425 on a soy-free diet (Wu et al., 2004; Bu and Lephart, 2005). Simi- shift towards the use of lipids as fuel source were two important 446
426 larly, Long-Evans rats or CD-1 male mice fed with dietary soy (with contributing factors for the leanness observed in mice exposed to 447
UN
427 serum levels of genistein and daidzein reaching 0.5 ␮M and equol dietary phytoestrogens (Cederroth et al., 2007). This decrease in 448
428 about 10 ␮M) have 50% decreased adipose weight (Lephart et al., fat abundance correlates with an increased activation, in periph- 449
429 2004a; Cederroth et al., 2007). In addition, dietary supplementa- eral tissues, of the AMP-activated protein kinase (AMPK) and its 450
430 tion with 500–1500 ppm of genistein, with a serum equivalent of downstream target Acetyl-CoA carboxylase (ACC) (Cederroth et al., 451
431 about 2 ␮M, decreases fat pad weights by 50% in C57/BL6 mice (Naaz 2008), two enzymes which are key regulators of fatty acid oxida- 452
432 et al., 2003). The effects on adiposity are dose-dependent, since the tion (Winder and Hardie, 1996; Ruderman and Prentki, 2004). In 453
433 magnitude of adipose weight reduction correlates with increasing these mice, two targets of AMPK, peroxisome proliferator activated 454
434 doses of soy-derived phytoestrogens (Lephart et al., 2004b). Simi- receptor (PPAR)␥ co-activator (PGC)-1␣ and (PPAR)␣, which regu- 455
435 larly, subcutaneous injections of genistein (8–200 mg/kg/day) for 21 late mitochondrial and peroxisomal metabolism respectively (Zong 456
doi:10.1016/j.mce.2009.02.027
G Model
Table 4
Clinical Studies performed using dietary supplementation with phytoestrogens or isoflavones.
Clinical Studies performed using dietary supplementation with phytoestrogens or isoflavones
Model Number of Duration Isoflavone intake Serum or urinary isoflavone Metabolic effects References
individuals
Postmenopausal women Total = 136 6 months Isoflavones Serum genistein: 0.32 (0.28) No effects on TC, TG Wu et al. (2006)
(75 mg/day) vs
placebo
Daidzein: 0.89 (0.27) Lower F/BMI
Equol: 0.19 (0.07) Increased HDL
Glycitein: 0.19 (0.06)
Postmenopausal women Total = 34 2 months Isoflavones Urinary genistein: 12.2 (0.65)

(50 mg/day) vs
placebo
Daidzein: 8.1 (0.22)
Equol: No effects on W, Weickert et al. (2006)
OF
F/BMI, G, I
- Equol producers: 5.8 (0.237)
- Non-producers: 0.245 (0.160)
Healthy Postmenopausal women Total = 117 8 weeks Isoflavones vs Urinary genistein: 7.27 (0.42) No effects on G, I, TC, Hall et al. (2006)
placebo LDL, HDL, TG
Daidzein: 5.76 (0.22)
RO
Equol:
- Equol producers: 2.61 (0.13)
- Non-producers: 0.15 (0.094)
Postmenopausal women 38 (40) 3 months Isoflavones ND Dalais et al. (2003)

(118 mg/day) vs
placebo
No effects in TC, HDL
DP
Lower LDL, TG
Postmenopausal women with Total = 32 12 weeks Phytoestrogens ND No effects on W, G, Jayagopal et al. (2002)
type 2 diabetes vs placebo HDL, TG
Lower I, TC, LDL
Serum isoflavone values are expressed in ␮M. Urinary isoflavone values are expressed in mM. For control groups the number of individuals (n) and the corresponding serum
TE
or urinary isoflavone values are shown in parentheses.
457 et al., 2002; Lin et al., 2005), were preferentially upregulated in In rat models of obesity and type 2 diabetes (SHR/N-cp rats and 474
458 adipose tissue (Cederroth et al., 2008). Additionally, in vitro expo- ZDFxSHHF rats), treatment with isoflavones decreases glycemia or 475
459 sure of cultured 3T3-L1 adipocytes to genistein has been reported circulating insulin levels (Ali et al., 2005; Davis et al., 2005). Sim- 476
to significantly activate AMPK and ACC (Hwang et al., 2005). Fur- ilarly, in mice models of obesity and diabetes, treatment with soy
EC
460 477
461 thermore, in vitro studies using isolated rat adipocytes have shown protein or genistein lowers glycemia (Aoyama et al., 2000a; Ae Park 478
462 that genistein stimulates lipolysis through the inhibition of cAMP et al., 2006). 479
463 phosphodiesterases (Szkudelska et al., 2000). Similarly, it has been Potential mechanisms by which dietary soy may improve 480
464 recently shown that an isoflavone-free peptide mixture from black glucose metabolism have been recently proposed. Dietary soy 481
465 soybean (BSP) significantly activates both AMPK and ACC in C2C12 improves insulin sensitivity by increasing glucose uptake prefer- 482
RR
466 myocytes, in a dose dependent manner (Jang et al., 2008). Interest- entially in skeletal muscles (Cederroth et al., 2008). This improved 483
467 ingly, a high fat diet containing 10% of this same BSP fed to mice insulin responsiveness in mice exposed to dietary soy may take 484
468 for 13 weeks, led to AMPK activation in WAT of mice compared to place, at least in part, by an improvement of the PI(3)K-Akt sig- 485
469 control animals. naling by the dietary soy-activated AMPK (Cederroth et al., 2008). 486
470 Fewer studies have evaluated the effects of soy and phytoe- Whether these effects are due to soy proteins or phytoestrogens 487
471 strogens on glucose homeostasis. Rats fed with SPI exhibit lower remains unknown. 488
CO
472 glucose and insulin levels in the plasma (Hurley et al., 1998) as well The effects of soy and phytoestrogens on the pancreas are less 489
473 as increased peripheral insulin sensitivity (Lavigne et al., 2000). known. Recently, an in vivo study has evaluated ␤-cell function 490
Table 5
Clinical Studies performed using dietary supplementation with ␤-conglycitin.
Clinical Studies performed using dietary supplementation with ␤-conglycitin

UN
Model Number of individuals Duration Design Metabolic effects References
Hyperlipidemic male and women 69 (69) 12 weeks Beta-conglycinin vs No effects on W, F/BMI, G, I, TC, Kohno et al. (2006)
casein LDL decreased TG, FFA
increased HDL
Obese male and women 24 (22) 12 weeks Beta-conglycitnn vs No effects on TC, LDL, HDL, TG Kohno et al. (2006)
casein lower W, F/BMI, FFA
For control groups, the number of individuals (n) is shown in parentheses.
doi:10.1016/j.mce.2009.02.027
8
MCE 7153 1–13

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doi:10.1016/j.mce.2009.02.027
Table 6
Animal studies performed using dietary supplementation with dietary soy.
Animal Studies performed using dietary supplementation with dietary soy
Species Duration (days) Dose (ppm) Total serum Number of Weight Food intake Fat mass Glycemia Circulating insulin Reference
isoflavone levels animals
Male rats
Long-Evans Life long 600 ∼7.07 ND Decreased Increased Decreased ND Decreased Lephart et al. (2004a)
UN
Sprague–Dawley
Female OVX rats

Life long 600 ∼8.7
∼3.3
57 (57) Decreased No effect ND ND ND Weber et al. (2001)
C
OVX Long-Evans 42 days 600 ND Decreased Increased Decreased ND ND Bu et al. (2005)
Male mice
OR ∼10
C.R. Cederroth, S. Nef / Molecular and Cellular Endocrinology xxx (2009) xxx–xxx
CD-1 Life long 600 12 (12) Decreased Increased Decreased ND ND Cederroth et al. (2007)
CD-1 Life long 600 ∼10 5–14 Decreased ND Decreased No effect Decreased a , b Cederroth et al. (2008)
(5–19)
ARTICLE IN PRESS
R
Female mice
CD-1 Life long 600 ∼10 12 (12) Decreased ND Decreased ND ND Cederroth et al. (2007)
EC
Studies using dietary soy are distinguished from SPI in that they include analysis of serum isoflavone abundance, while all the presented studies in rodents using SPI, presence or absence of isoflavones has not been measured. For
Q4 clarity, data on serum lipid profiles are not presented. Abbreviations: OVX, ovariectomized; ND, not determined. Symbols: * Total isoflavone content.
a
TE
Increased glucose tolerance.
b
Increased insulin sensitivity. Total serum isoflavone values are expressed in ␮M. For control groups, the number of individuals (n) is shown in parentheses.
DP
Table 7
Animal studies performed using dietary supplementation with soy protein isolates (SPI).
RO
OF
Animal studies performed using dietary supplementation with soy protein isolates (SPI)
Species Duration (days) Dose (% SPI) Number of animals Weight Food intake Fat mass Glycemia Circulating insulin Reference
(controls)
Male rats
Sprague–Dawley 28 22.6 10 (10) Decreased ND Decreased Decreased Decreased Hurley et al. (1998)
Wistar 28 22.9 20 (20) No effect No effect ND Decreased Decreased a , b Lavigne et al. (2000)
Wistar 10 22.4 8 (8) No effect No effect No effect No effect No effect Nagasawa et al. (2003)
Sprague–Dawley 28 41.1 8 (6) No effect No effect No effect Decreased ND Aoyama et al. (2000b)
Sprague–Dawley 180 30 8 (8) Decreased ND No effect No effect No effect Torre-Villalvazo et al. (2008)
Sprague–Dawley on a HFD 180 30 8 (8) Decreased ND Decreased No effect No effect Torre-Villalvazo et al. (2008)
Male mice
Obese yellow KK-Ay 14 41.6 10 (10) No effect No effect Decreased No effect ND Aoyama et al. (2000a)
Obese yellow KK-Ay 28 41.1 12 (12) No effect ND Decreased ND ND Aoyama et al. (2000b)
Obese yellow KK-Ay 63 50 10 (10) Decreased No effect Decreased Decreased Decreased Nordentoft et al. (2008)
CD-1 Life long ND# 10 (13) Decreased Increased Decreased ND ND a Ruhlen et al. (2008)
Female mice
CD-1 Life long ND# 10 (13) Decreased ND Decreased ND ND Ruhlen et al. (2008)
For clarity, data on serum lipid profiles are not presented. In the following studies, serum isoflavone levels were not analyzed. Abbreviations: OVX, ovariectomized; SPI, soy protein isolate; ND, not determined.
a
b
Increased insulin sensitivity.
#
Estrogenic activity tested in vitro. For control groups, the number of individuals (n) is shown in parentheses.
G Model
Dolinoy et al. (2006)
Dolinoy et al. (2006)

after exposure of CD-1 male mice to dietary soy. Dietary soy lowers
Ae Park et al. (2006)

491
Penza et al. (2006)
Naaz et al. (2003)

Naaz et al. (2003)
Naaz et al. (2003)
Naaz et al. (2003)
pancreatic insulin content, while high glucose-stimulated insulin 492
secretion is unchanged, suggesting that insulin secretion is ame- 493
liorated (Cederroth et al., 2008). Although it is not clear whether

Reference
494
these beneficial effects are due to the isoflavones themselves or 495
other components of soy proteins, recent reports indicate that the 496
isoflavone genistein may itself have a direct beneficial effect on 497
pancreatic ␤-cells. For example, genistein has been shown to stim- 498
ulate insulin secretion in the insulin-secreting cell lines INS-1 and 499
Circulating
No effectc
MIN6 and in mouse pancreatic islets, at nano- and micromolar con- 500
insulin
NDa,b
centrations (Liu et al., 2006). In addition, genistein has been also 501
ND
ND
ND
ND
ND
ND
reported to prevent cytokine-induced cell damage in rat insuli- 502
noma cells (RIN cells) (Kim et al., 2007). Genistein and daidzein have 503
been shown to prevent diabetes onset in non-obese diabetic (NOD) 504

Decreased
Glycemia
mice by preserving pancreatic ␤ cell function (Choi et al., 2008). 505
OF
Similarly, Lee (2006) recently reported that in streptozotocin- 506
ND
ND
ND
ND
ND
ND
ND
induced diabetic rats, supplementation with genistein (600 mg/kg 507
of diet) cause a 2 fold increase in plasma insulin levels. Collectively, 508
these data suggest that dietary soy and phytoestrogens may have 509
Decreased
Decreased
Decreased
Increased
therapeutic significance in reducing the severity of diabetes, and

No effect
510
Fat mass
No effects on insulin sensitivity. Serum genistein values are expressed in ␮M. For control groups, the number of individuals (n) for is shown in parentheses.
improving ␤-cell survival and function. However, further research
RO
511
ND
ND
ND
is needed, first to confirm and then to analyze in detail, how phy- 512
Q5 For clarity, data on serum lipid profiles are not presented. Abbreviations: OVX, ovariectomized; ND, not determined. Symbols: * Total isoflavone content.
toestrogens exert anti-hyperglycemic actions through pancreatic 513
␤-cells. 514
Food intake
No effect
No effect
9. Central actions of phytoestrogens 515

DP
ND
ND
ND
ND
ND
ND
Whether or not soy-derived compounds modulate energy 516
expenditure via the CNS is unclear, but recent data suggest that 517
Decreased
Decreased
some effects may be centrally mediated. In mice or rats fed 518

No effect
No effect
Weight
soy-rich diets, feeding behavior and locomotor activity were sig- 519
nificantly affected, suggesting that the central regulation of energy

ND
ND
ND
ND
520
balance in the hypothalamus may be modulated by soy or phy- 521

TE
toestrogens (Lephart et al., 2003; Cederroth et al., 2007). For 522
example, in mice exposed to dietary soy, the increased loco- 523

Number of
motor activity and preferential use of lipids as fuel source is 524

animals
10 (10)
associated with a 40% decrease in mRNA levels of AgRP in the

4 (4)
4 (4)
4 (4)
4 (4)
525
ND
ND
20
hypothalamus (Cederroth et al., 2007). AgRP is a key neuropep- 526
tide regulating energy expenditure in the arcuate nucleus of the

EC
527
hypothalamus (Stutz et al., 2005). Mice lacking AgRP, or having 528
50% reduction of AgRP levels in the hypothalamus, display an

Serum genistein
529
increased metabolic rate, lipid utilization and locomotor activity 530

2.55 (0.08)
3.81 (0.08)
1.79 (0.08)
1.02 (0.08)
(Makimura et al., 2002; Wortley et al., 2005). In a similar study, 531
rats exposed to the same soy-based diet exhibited higher expres-

levels
532
0.09
RR
ND
ND
ND
Animal Studies performed using dietary supplementation with Genistein
Animal studies performed using dietary supplementation with genistein.
sion of transcripts for NPY (an approximately 40% increase) in 533
the arcuate and paraventricular nuclei of the hypothalamus. NPY 534
is an orexigenic neuropeptide known to stimulate food intake 535

Dose ppm
both in rodents and humans (Schwartz et al., 2000). Recently, it 536
has been reported that an isoflavone-free peptide mixture from 537

800
2000
250
250
300
500
1000
1500
black soybean (BSP) significantly decreased food intake in rats and 538
CO
leptin-deficient ob/ob mice (Jang et al., 2008). The authors pre- 539
sented evidence that BSP has anorectic effects in association with 540
the induction of hypothalamic STAT3 phosphorylation, a major

18, during gestation
18, during gestation
541
pathway involved in suppression of food intake and energy expen- 542

Duration (days)
diture (Bates and Myers, 2003). Further studies are needed to 543
No effects on glucose tolerance.
ascertain whether or not soy peptides or dietary phytoestrogens 544

12 days
act directly on the hypothalamus to improve lipid and glucose

UN
545
metabolism.
42
15
546
10. Potentially adverse effects in consuming soy and 547

Female OVX Mice
Db/Db-C57BL/KSJ
soy-derived phytoestrogens 548

Female Mice
Male mice
The extent to which soy food and its bioactive component 549
C57BL/6
C57BL/6
Species
Table 8
genistein pose potential health risks is still a matter of debate

Avy /a
Avy /a
550
a
(Setchell, 2006). In fact, the initial recognition and identification 551
doi:10.1016/j.mce.2009.02.027
G Model
Table 9
Animal studies performed using subcutaneous injections or gavage of genistein.
Animal studies performed using subcutaneous injections or gavage of genistein
Species Duration Dose Serum Number of Weight Food intake Fat mass Reference
(days) genistein levels animals
Subcutaneous injections
Female OVX mice
C57BL/6 21 20 mg/kg/day ND 10 (10) No effect No effect No effect Naaz et al. (2003)
80 mg/kg/day ND 10 (10) No effect No effect Decreased Naaz et al. (2003)
200 mg/kg/day ND 10 (10) No effect No effect Decreased Naaz et al. (2003)
Oral gavage
Male mice
C57BL/6 mice 15 50 ␮g/kg 35 (28) 20 (20) No effect No effect No effecta,b Penza et al. (2006)
500 ␮g/kg 66 (28) 20 (20) No effect No effect Increaseda,b Penza et al. (2006)
5,000 ␮g/kg 74 (28) 20 (20) No effect No effect Increaseda,b Penza et al. (2006)
50,000 ␮g/kg 98 (28) 20 (20) No effect No effect Increaseda,b Penza et al. (2006)
OF
200,000 ␮g/kg 223 (28) 20 (20) Decreased Decreased Decreased a,c Penza et al. (2006)
Female mice
C57BL/6 15 50 ␮g/kg 35 (28) 20 (20) No effect No effect No effecta,b Penza et al. (2006)
500 ␮g/kg 66 (28) 20 (20) No effect No effect No effecta,b Penza et al. (2006)
5,000 ␮g/kg 74 (28) 20 (20) No effect No effect No effecta,b Penza et al. (2006)
50,000 ␮g/kg 98 (28) 20 (20) No effect No effect No effect a,b Penza et al. (2006)
RO
200,000 ␮g/kg 223 (28) 20 (20) Decreased Decreased Decreaseda,c Penza et al. (2006)
For clarity, data on serum lipid profiles are not presented. In the following studies, serum glucose and insulin were not analyzed. Abbreviations: OVX, ovariectomized; ND, not
determined.
a
No effects on glucose tolerance.
b
No effects on insulin sensitivity. Serum genistein values are expressed in nM. For control groups, the number of individuals (n) and the corresponding serum genistein
values are shown in parentheses.
c
Increased insulin sensitivity.
DP
552 of phytoestrogens as bioactive compounds was made in the 1940s particular because the route of administration differs (oral versus 576
553 when it was found that formononetin, an isoflavone present in red injection) resulting in the bypass of the intestines, which provide 577
554 clover (Trifolium pratense L.), caused a devastating infertility syn- a limiting barrier to the bioavailability of isoflavones. This is par- 578
555 drome in sheep grazing in clover pasture (Bennetts et al., 1946). ticularly relevant since the two main isoflavones, genistein and 579
556 In another study, high levels of phytoestrogens were found in the daidzein, are present in soy as ␤-D-glycosides, namely genistin and 580
TE
557 leaves of stunted desert annuals in a dry year, leading ultimately diadzin (Fig. 1). Both genistin and daidzin are biologically inactive 581
558 to impaired reproduction when ingested by the California quail and require the hydrolyzation of the glycosidic bond by glucosi- 582
559 (Lophortyx californicus). In wet years these quails bred normally and dases of the intestinal bacteria to produce the biologically active 583
560 phytoestrogens were largely absent in these herbs (Leopold et al., aglycone forms. 584
561 1976). In humans, the use of soy or purified phytoestrogens in women 585
EC
562 Numerous studies in rodents clearly show that purified genis- at high risk of, or diagnosed with, breast cancer as well as in infants 586
563 tein (delivered by subcutaneous or intraperitoneal injections) has fed with soy-based formula are legitimate areas of concern. Con- 587
564 detrimental effects. The incidence of uterine carcinoma increased cerning breast cancer, caution is warranted since the available data 588
565 by 31% in neonatal mice treated subcutaneously with 50 mg/kg/day are conflicting, and there is evidence for both inhibitory and stim- 589
566 of genistein for a 5-day period (Newbold et al., 2001). Female mice ulatory effects of dietary soy on breast cancer cell growth (Duffy 590
567 that received subcutaneous injections of 50 mg/kg/day postnatally, et al., 2007). In vivo data from animals suggest that genistein may 591
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568 while remaining fertile, could not deliver pups and had multi- interfere with the inhibitory effect of tamoxifen on breast cancer 592
569 oocyte follicles (MOFs) (Jefferson et al., 2005, 2007). In adult male cell growth (Ju et al., 2002; Liu et al., 2005), while epidemiolog- 593
570 rats, exposure to dietary soy decreased androgen levels and prostate ical studies in humans show that exposure in early childhood or 594
571 weight (Weber et al., 2001). Finally, it has been shown in female early adolescence protects against the development of breast can- 595
572 mice that dietary phytoestrogens accelerated the time of vaginal cer as an adult (Wu et al., 2002). Concerning soy-based formula, 596
573 opening in immature CD-1 mice (Thigpen et al., 2003). However, caution should prevail, even though it has been consumed by mil- 597
CO
574 with the exception of dietary soy experiments, most of these find- lions of infants over the past decades without apparent detrimental 598
575 ings may have little relevance to humans consuming soy food, in effects. Infancy is a very sensitive period for endocrine disruption, 599
Table 10
Animal studies performed using dietary supplementation with pure soy proteins.
Animal studies performed using Dietary supplementation with soy proteins (isoflavone-free)
UN
Species Duration Dose (%) Number of Weight Fat mass Glycemia Circulating Reference
(days) animals insulin
ICR 28 23.7 (␤-conglycinin) 10 (10) Decreased No effect Decreased Decreased Moriyama et al. (2004)
ICR 28 21.9 (glycinin) 10 (10) Decreased No effect No effect No effect Moriyama et al. (2004)
yellow KK-Ay 28 23.7 (␤-conglycinin) 10 (10) Decreased No effect No effect Decreased Moriyama et al. (2004)
yellow KK-Ay 28 21.9 (glycinin) 10 (10) Decreased No effect No effect No effect Moriyama et al. (2004)
Obese C57BL/6 91 Black soy protein 9 (9) Decreased No effect ND ND Jang et al. (2008)
For clarity, data on serum lipid profiles are not presented. Food intake was not measured in these studies. In the following studies, serum glucose and insulin were not
analyzed. For control groups, the number of individuals (n) is shown in parentheses.
doi:10.1016/j.mce.2009.02.027
G Model
600 and exposure to significant levels of phytoestrogens may ultimately Alonso-Magdalena, P., Morimoto, S., Ripoll, C., Fuentes, E., Nadal, A., 2006. The estro- 665
genic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and 666
601 lead to adult onset diseases.
induces insulin resistance. Environ. Health Perspect. 114, 106–112. 667
Alonso-Magdalena, P., Ropero, A.B., Carrera, M.P., Cederroth, C.R., Baquie, M., Gau- 668
thier, B.R., Nef, S., Stefani, E., Nadal, A., 2008. Pancreatic insulin content regulation 669
602 11. Summary and conclusion
by the estrogen receptor ER alpha. PLoS ONE 3, e2069. 670
Anderson, J.W., Johnstone, B.M., Cook-Newell, M.E., 1995. Meta-analysis of the effects 671
603 Current evidence from animal and human studies suggests that of soy protein intake on serum lipids. N. Engl. J. Med. 333, 276–282. 672
Anderson, J.W., Hoie, L.H., 2005. Weight loss and lipid changes with low-energy 673
604 diets rich in soy and phytoestrogens have beneficial effects on many
diets: comparator study of milk-based versus soy-based liquid meal replacement 674
605 aspects of diabetes and obesity. In animal studies, soy and phy- interventions. J. Am. Coll. Nutr. 24, 210–216. 675
606 toestrogens are effective at reducing adipose tissue and improving Anderson, J.W., Fuller, J., Patterson, K., Blair, R., Tabor, A., 2007. Soy compared to 676
607 glucose uptake. However, available data from human studies do not casein meal replacement shakes with energy-restricted diets for obese women: 677
randomized controlled trial. Metabolism 56, 280–288. 678
608 offer clear support, and further research is required before a firm Aoyama, T., Fukui, K., Nakamori, T., Hashimoto, Y., Yamamoto, T., Takamatsu, K., 679
609 conclusion can be made about the benefits of soy and phytoestro- Sugano, M., 2000a. Effect of soy and milk whey protein isolates and their 680
610 gens in the context of adiposity control and glucose metabolism. hydrolysates on weight reduction in genetically obese mice. Biosci. Biotechnol. 681
Biochem. 64, 2594–2600. 682
611 The specific soy protein components that may lead to metabolic Aoyama, T., Fukui, K., Takamatsu, K., Hashimoto, Y., Yamamoto, T., 2000b. Soy protein 683
OF
612 improvements have yet to be determined. Phytoestrogens appear isolate and its hydrolysate reduce body fat of dietary obese rats and genetically 684
613 to have beneficial actions both on glucose and lipid metabolism obese mice (yellow KK). Nutrition 16, 349–354. 685
Atkinson, C., Frankenfeld, C.L., Lampe, J.W., 2005. Gut bacterial metabolism of the soy 686
614 but additional micronutriments such as saponins, phytosterols, isoflavone daidzein: exploring the relevance to human health. Exp. Biol. Med. 687
615 trypsin inhibitors, as well as amino acid and protein composi- (Maywood) 230, 155–170. 688
616 tion, may have additive or synergistic effects. Additional studies Bailey, C.J., Matty, A.J., 1972. Glucose tolerance and plasma insulin of the rat in relation 689
to the oestrous cycle and sex hormones. Horm. Metab. Res. 4, 266–270. 690
617 both in humans and animals will be required to identify precisely
Bailey, C.J., Ahmed-Sorour, H., 1980. Role of ovarian hormones in the long-term 691
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618 which components and constituents have beneficial roles. Unfortu- control of glucose homeostasis. Effects of insulin secretion. Diabetologia 19, 692
619 nately, comparisons between different animal or clinical studies are 475–481. 693
Barros, R.P., Machado, U.F., Warner, M., Gustafsson, J.A., 2006. Muscle GLUT4 regula- 694
620 hampered by the lack of standardization of soy nomenclature, the
tion by estrogen receptors ERbeta and ERalpha. Proc. Natl. Acad. Sci. U.S.A. 103, 695
621 different formulations, doses, routes of exposure, time and duration 1605–1608. 696
622 of exposure as well as by major differences in the subsequent analy- Bates, S.H., Myers Jr., M.G., 2003. The role of leptin receptor signaling in feeding and 697
623 ses performed to evaluate the effects and elucidate the mechanisms neuroendocrine function. Trends Endocrinol. Metab. 14, 447–452. 698
Bennetts, H.W., Underwood, E.J., Shier, F.L., 1946. A specific breeding problem of 699
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624 by which phytoestrogens and soy potentially improve glucose and sheep on subterranean clover pastures in Western Australia. Austr. Vet. J. 22, 700
625 lipid metabolism. All of these variables make it difficult to compare 2–12. 701
626 and evaluate the putative beneficial effects of soy and phytoestro- Bhathena, S.J., Velasquez, M.T., 2002. Beneficial role of dietary phytoestrogens in 702
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627 gens on metabolism. Clearly more standardized studies, involving Bu, L., Setchell, K.D., Lephart, E.D., 2005. Influences of dietary soy isoflavones on 704
628 both basic research and clinical trials, are needed. Given the rapidly metabolism but not nociception and stress hormone responses in ovariec- 705
629 increasing prevalence and societal impact of metabolic disorders, tomized female rats. Reprod. Biol. Endocrinol. 3, 58. 706
Bu, L.H., Lephart, E.D., 2005. Effects of dietary phytoestrogens on core body temper- 707
630 such studies should have high priority. ature during the estrous cycle and pregnancy. Brain Res. Bull. 65, 219–223. 708
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Caldwell, C.R., Britz, S.J., Mirecki, R.M., 2005. Effect of temperature, elevated car- 709
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631 Acknowledgments of dwarf soybean [Glycine max (L.) Merrill] grown in controlled environments. J. 711
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632 We thank Prof. J.-D. Vassalli for critical comments on the Carani, C., Qin, K., Simoni, M., Faustini-Fustini, M., Serpente, S., Boyd, J., Korach, K.S., 713
Simpson, E.R., 1997. Effect of testosterone and estradiol in a man with aromatase 714
633 manuscript. Authors were funded by grants from the Swiss National deficiency. N. Engl. J. Med. 337, 91–95. 715
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634 Science Foundation, Foundation Gertrude von Meissner, Fondation Case, A.M., Reid, R.L., 2001. Menstrual cycle effects on common medical conditions. 716
635 Ernst & Lucie Schmidheiny, the Sir Jules Thorn Charitable Overseas Compr. Ther. 27, 65–71. 717
Cederroth, C.R., Vinciguerra, M., Kuhne, F., Madani, R., Doerge, D.R., Visser, T.J., Foti, 718
636 Trust Reg., Schaan and the Cloëtta foundation. Serge Nef is a founder
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MCE 7153 1–13 ARTICLE IN PRESS

Contents lists available at ScienceDirect

Molecular and Cellular Endocrinology

2 Soy, phytoestrogens and metabolism: A review

21 1. Metabolic diseases and therapeutic alternatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

24 4. Soy consumption and phytoestrogen levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

30 10. Potentially adverse effects in consuming soy and soy-derived phytoestrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

niﬁcant contributor to worldwide morbidity. In western societies, 44

ing health beneﬁts. Usually dietary intervention to control excess 53

0303-7207/$ – see front matter © 2009 Published by Elsevier Ireland Ltd.

57 health beneﬁts can be gained from dietary proteins and bioac-

91 are fairly well understood. To understand these intricate relation-

sponding bioactive aglycones (genistein and daidzein). Only the 162

animals (Setchell, 1998). In rodents, equol is the major circulat- 168

119 humans and rodents supporting or refuting the potential ben-

metabolism. As mentioned, the abundance of isoﬂavones varies according 180

183 can be dissociated from soy-proteins using alcohol extraction

186 ability of phytoestrogen content found in soy products [0.1–5 mg

Compound Relative binding afﬁnity Relative transactivation

ER␣ ER␤ ER␣ ER␤

17␤-estradiol 100 100 100 100

Isoﬂavones Genistein 4 87 198 182

Endocrine disruptors Bisphenol A 0.01 0.01 50 41

transporter 4 (Glut4), a key molecule for the import of glucose in 296

and duration), the capacity of individuals to produce equol and

the genetic susceptibility. Clearly more standardized studies are 390

346 in Asian populations has drawn attention towards soy, which is a

Epidemiological studies evaluating the effects of soy or isoﬂavones on human metabolism.

Epidemiological studies evaluating the effects of soy or isoﬂavones on human metabolism

Model Number of Dose Metabolic Effects References

intervention F/BMI, G, I, TC, LDL,

Clinical Studies performed using dietary supplementation with phytoestrogens or isoﬂavones

Postmenopausal women Total = 34 2 months Isoﬂavones Urinary genistein: 12.2 (0.65)

Postmenopausal women 38 (40) 3 months Isoﬂavones ND Dalais et al. (2003)

or urinary isoﬂavone values are shown in parentheses.

Clinical Studies performed using dietary supplementation with ␤-conglycitin

Model Number of individuals Duration Design Metabolic effects References

MCE 7153 1–13

Animal Studies performed using dietary supplementation with dietary soy

Female OVX rats

Dolinoy et al. (2006)

Dolinoy et al. (2006)

Ae Park et al. (2006)

Penza et al. (2006)

Naaz et al. (2003)

secretion is unchanged, suggesting that insulin secretion is ame- 493

liorated (Cederroth et al., 2008). Although it is not clear whether

these beneﬁcial effects are due to the isoﬂavones themselves or 495

isoﬂavone genistein may itself have a direct beneﬁcial effect on 497

been shown to prevent diabetes onset in non-obese diabetic (NOD) 504

mice by preserving pancreatic ␤ cell function (Choi et al., 2008). 505

of diet) cause a 2 fold increase in plasma insulin levels. Collectively, 508

therapeutic signiﬁcance in reducing the severity of diabetes, and

improving ␤-cell survival and function. However, further research

toestrogens exert anti-hyperglycemic actions through pancreatic 513

9. Central actions of phytoestrogens 515

Whether or not soy-derived compounds modulate energy 516

some effects may be centrally mediated. In mice or rats fed 518

niﬁcantly affected, suggesting that the central regulation of energy

balance in the hypothalamus may be modulated by soy or phy- 521

toestrogens (Lephart et al., 2003; Cederroth et al., 2007). For 522

example, in mice exposed to dietary soy, the increased loco- 523