Gender Dimorphism in Aspartame-Induced Impairment of Spatial Cognition and Insulin Sensitivity

Abstract

Previous studies have linked aspartame consumption to impaired retention of learned behavior in rodents. Prenatal exposure to aspartame has also been shown to impair odor-associative learning in guinea pigs; and recently, aspartame-fed hyperlipidemic zebrafish exhibited weight gain, hyperglycemia and acute swimming defects. We therefore investigated the effects of chronic lifetime exposure to aspartame, commencing in utero , on changes in blood glucose parameters, spatial learning and memory in C57BL/6J mice. Morris Water Maze (MWM) testing was used to assess learning and memory, and a random-fed insulin tolerance test was performed to assess glucose homeostasis. Pearson correlation analysis was used to investigate the associations between body characteristics and MWM performance outcome variables. At 17 weeks of age, male aspartame-fed mice exhibited weight gain, elevated fasting glucose levels and decreased insulin sensitivity compared to controls (P<0.05). Females were less affected, but had significantly raised fasting glucose levels. During spatial learning trials in the MWM (acquisition training), the escape latencies of male aspartame-fed mice were consistently higher than controls, indicative of learning impairment. Thigmotactic behavior and time spent floating directionless was increased in aspartame mice, who also spent less time searching in the target quadrant of the maze (P<0.05). Spatial learning of female aspartame-fed mice was not significantly different from controls. Reference memory during a probe test was affected in both genders, with the aspartame-fed mice spending significantly less time searching for the former location of the platform. Interestingly, the extent of visceral fat deposition correlated positively with non-spatial search strategies such as floating and thigmotaxis, and negatively with time spent in the target quadrant and swimming across the location of the escape platform. These data suggest that lifetime exposure to aspartame, commencing in utero, may affect spatial cognition and glucose homeostasis in C57BL/6J mice, particularly in males.

Non-caloric artificial sweeteners and the microbiome: findings and challenges

“…Some examples of non-favorable NAS metabolic effects suggested in such models include works by Swithers and colleagues, who demonstrated weight gain in rats following consumption of saccharin, 12,22 acesulfame-potassium (AceK) 22 or stevia, 11 with saccharin also linked to increased adiposity. 12 Increased weight gain in rats consuming saccharin or aspartame was also reported by Bertoluci and colleagues, 23 while aspartame consumption was shown to increase weight gain and adiposity in mice, as reported by Al-Mohanna and colleagues 24 and by Shibata and colleagues, 25 respectively. Rats consuming sucralose were also shown by Schiffman and colleagues 26 to gain more weight, a finding that initiated intense debate.…”

“…Rats consuming sucralose were also shown by Schiffman and colleagues 26 to gain more weight, a finding that initiated intense debate. 27 In addition to weight gain, both saccharin and aspartame have been associated with impaired glucose homeostasis in mice, 24,28,29 and aspartame was also shown to induce hyperinsulinemia, 25 impaired insulin tolerance 24,28 and worsened atherosclerosis in genetically-susceptible (ApoE ¡/¡ ) mice. 30,31 In contrast, Flatt and colleagues described anti-hyperglycemic and antihyperinsulinemic effects for saccharin in genetically obese (ob/ob) mice, coupled with attenuation of weight gain.…”

Low-calorie sweetener use and energy balance: Results from experimental studies in animals, and large-scale prospective studies in humans

“…Mitsutomi et al [26], examining the impact of exposure to a combination of non-nutritive sweeteners (‘NNS’: 99% erythritol and 1% aspartame) in mature C57BL/6 mice with diet-induced obesity, reported not only dramatically higher epididymal white tissue mass in the NNS-exposed group – despite comparable food intake – but also insulin levels that were double those in a plain-water control group [26]. Similarly, in 2012 Collison et al, studying C57BL/6J mouse offspring exposed to aspartame from conception through age 17 weeks, reported that aspartame exposure increased percent weight gain and reduced insulin sensitivity in males, and markedly increased visceral fat and fasting glucose in both sexes, even in the absence of increased weight gain in females [35]. In a second experiment also published in 2012, Collison et al [25] reported significantly increased percent weight change in males – but not females – exposed to either ASP alone or the combination of ASP + MSG [25].…”

“…Two-thirds of RCTs reviewed by Miller et al [38], however, had included either disproportionately few [39–46] or no males [47–50], even though animal studies have shown greater weight gain following LCS exposure in males, compared with females [19,35]. Similarly, ethnic minorities – such as African Americans and Mexican Americans – and lower-income participants have typically been underrepresented in RCTs, even though obesity and diabetes prevalence is higher in these groups [51–53].…”

The effect of sugar and artificial sweetener on molecular markers of metabolic syndrome: a mice study

“…In contrary, this research also mentioned that aspartame acted as a chemical stressor and raised oxidative stress leading to inflammation (Choudhary and Devi 2015). Other studies also demonstrated that aspartame consumption could cause an increment of fat and body mass (Collison et al, 2012;Feijo et al, 2013), liver damage, and non-alcoholic fatty liver disease (NAFLD) (Abhilash et al, 2011). A study by Yang (2010) proposed that the sweet response produced after consuming artificial sweetener could increase the appetite and reduce satiety, which finally led to obesity development.…”