In general, this study demonstrates that either dietary isoflavone exposure or equol alone effectively decreased body weight and WAT deposition in females regardless of ovarian status, which is similar to that reported previously [17
]. Of note, the primary isoflavone present in the serum of rats fed a soy-rich diet is equol (Table ) while genistein and daidzein represent smaller percentages of the total isoflavone count [18
]. When equol is injected alone, experiments 1, 4, and 5 demonstrate that body weight still decreased. Equol has body weight controlling effects in female rats is dependent on age and initiation of the diet treatments. Neurobehavioral influences may underlie the present effects due to ovarian status and the dosage of isoflavonoids administered [25
]. However, while equol's mechanism of action is unknown, evidence to support the role of ERβ's anti-adiposity in animals and humans has been reported [26
]. Moreover, animals fed soy-containing diets or administered genistein appears to alter food intake and metabolic hormones, body weight and adipose tissue deposition as well as lipid uptake into adipocytes by decreasing lipoprotein lipase (LPL) activity [18
]. Daidzein also appears to decrease LPL activity, increase lipolysis, and inhibit adipogenesis via estrogenic pathways [28
]. Furthermore, unpublished data by our lab demonstrates that equol's actions can be blocked by an ER antagonist. Tamoxifen, a SERM able to antagonize ERs [35
] is able to block the positive influence of equol in human monolayer fibroblasts.
This study also demonstrated that equol decreases depressive-related behavior in NOF females. Prior to equol injections in experiment 5, the Phyto-low animals demonstrated greater immobility and lower serotonin levels. These differences were reversed following equol injection as time immobile significantly decreased and serum serotonin levels significantly increased in the Phyto-low animals. This study is the first to test and report equol's potential effectiveness as an antidepressant using the PFST. The testing of other isoflavones such as quercitin or resveratrol in the PFST, while few in number, demonstrate that isoflavones have potential as antidepressant treatments [36
Equol's antidepressant potential demonstrated in the PFST, may be attributed to equol's estrogenic actions in the brain. ERβ is found in four brain regions associated with behavioral and mood disorders, the frontal cortex, amygdala, hippocampus, and the hypothalamic region [38
]. Following dietary isoflavone exposure equol levels in the frontal cortex are highest followed by hypothalamus, amygdala, and the hippocampus [42
], demonstrating an ability for equol to concentrate in these regions. Additionally, though the equol levels in the amygdala, hypothalamus, and hippocampus are lower, equol is still the primary isoflavone found in these regions, representing over 80 to 90% of the total isoflavone content of these brain areas [42
Remarkably, equol could potentially affect the concentration of serotonin. For example, Dewar et al., reported that equol was an effective inhibitor of rat liver monoamine oxidase [43
]. Since monoamine oxidase is responsible for the deamination of monoamines, including serotonin, this may account for the increase levels of this important neurotransmitter associated with the positive shift in depressive-like behaviors observed in the present study. Notably, this was shown in NOF females fed a soy-rich diet or equol administration alone in NOF females fed a low-soy diet. Specifically, the raphe nucles of the brain, which produces serotonin expresses ERβ [44
]. Lower serotonin levels are associated with depression in humans [45
]. Furthermore, the relationship between serum and CSF serotonin levels indicates potential for decreased serum serotonin concentrations to signify depression [45
]. Equol's ability to bind ERβ's in various brain regions may have increased serotonin levels and improved mobility intervals in the PFST suggesting equol's potential as an antidepressant agent that represents quite novel results.
It is noteworthy that ERβ-deficient mice express increased anxiety [49
] while administration of specific ERβ modulators in animal studies decrease anxiety and depression [40
]. Furthermore, in human studies of depressed subjects, fluoxetine treatment increased serum serotonin levels by 1.7-fold [52
], a value similar to that seen in experiment 5 in this study which may suggest a similar mechanism of action or potentially an increase in serotonin with enhanced catecholamine levels as reported by others in human studies [53
]. In any event, further study for the potential of equol's antidepressant actions is warranted.
However, the use of animals with varying ovarian status demonstrated that equol appears to have a defined range of effectiveness. For instance, ovarian status plays a role in equol treatment effectiveness. Equol is ineffective at decreasing depressive-related behavior in intact females or females ovariectomized shortly after puberty. Experiments 1-4 all displayed no significant differences in depressive-related behavior as measured by the PFST. Only experiment 5 showed any significant differences. Conversely, from this study it appears that equol has potential as an anti-obesity treatment regardless of ovarian status; however, as an antidepressant it appears to be effective only following NOF.
Menopause/ovarian failure is a normal part of the aging process [54
]. Depression and obesity are associated with menopause and affect both health and quality of life [3
]. Central obesity increases risk for many menopausal conditions such as cardiovascular disease or breast cancer [56
]. Depression can cause menopausal symptoms and associated conditions to feel and appear more serious [55
]. Additionally, more women are entering menopause prematurely due to either bilateral oophorectomy or cancer treatment [2
]. Severity of menopausal symptoms and the risk of certain diseases and conditions increase as age of menopause decreases [60
]. Furthermore, the five experiments in this study indicate that timing and manner of ovarian failure can affect treatment response. However, the extrapolation from animals to humans is not known.