Early-Life Exposure to Non-Nutritive Sweeteners and the Developmental Origins of Childhood Obesity: Global Evidence from Human and Rodent Studies.

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hyperlipidemia 1 endocrinologydiseases
obesity 38 endocrinologydiseases
childhood obesity 2 endocrinologydiseases
hyperglycemia 1 endocrinologydiseases

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childhood obesity 5753 marketing campaigns that promote NNS as a healthy alternative to sugar in an effort to curtail the childhood obesity epidemic [[26],[27]], and this appears to be a global phenomenon. In a 2011–2013 multi-national survey
childhood obesity 27170 cross-sectional study [[28]] and two RCTs [[31],[34]] have examined the relationship between NNS and childhood obesity outside of the US, Canada, or the UK. Therefore, it is unclear whether the reported findings are globally
hyperglycemia 19719 exposed to saccharin (1.35 g/L; 232 mg/kg/day) or control conditions. These male offspring also exhibited hyperglycemia and hyperlipidemia (elevated total cholesterol and triglycerides) characteristic of cardiometabolic
hyperlipidemia 19737 (1.35 g/L; 232 mg/kg/day) or control conditions. These male offspring also exhibited hyperglycemia and hyperlipidemia (elevated total cholesterol and triglycerides) characteristic of cardiometabolic disease. Moreover,
obesity 1163 cardio-metabolic health. Some observational studies suggest that children consuming NNS are at increased risk for obesity -related outcomes; however, others find no association or provide evidence of confounding. Fewer studies
obesity 2089 inconsistent evidence regarding the impact of early-life NNS exposure on the developmental programming of obesity and cardio-metabolic health. Further research and mechanistic studies are needed to elucidate these
obesity 2310 inform dietary recommendations for expectant mothers and children worldwide.1. IntroductionChildhood obesity is a health issue of increasing concern worldwide. One in three North American children are overweight
obesity 2645 and middle-income countries, particularly in parts of Asia, where the prevalence of overweight and obesity has increased consistently over the past three decades [[4],[5]]. This is alarming because obesity in
obesity 2744 obesity has increased consistently over the past three decades [[4],[5]]. This is alarming because obesity in childhood is a risk factor for many chronic diseases later in life [[6]]. An increasing number of
obesity 2887 many chronic diseases later in life [[6]]. An increasing number of children are being diagnosed with obesity -related conditions even before reaching adulthood, including type 2 diabetes, hypertension, chronic
obesity 3449 other endocrine pathways [[9]].Sugar intake is a nutritional exposure that is strongly associated with obesity among children and adults alike [[8],[13],[14],[15]]; hence, sugar substitutes or “non-nutritive sweeteners”
obesity 4940 childhood exposure to NNS worldwide, and their potential effects on weight gain, body composition, and obesity in human and animal studies. We also discuss current challenges and future research priorities in this
obesity 5763 campaigns that promote NNS as a healthy alternative to sugar in an effort to curtail the childhood obesity epidemic [[26],[27]], and this appears to be a global phenomenon. In a 2011–2013 multi-national survey
obesity 6988 children [[22]] compared to adults [[19]]. Table 1 summarizes 19 human studies reporting on NNS use and obesity -related outcomes in children, classified by study design. The majority were conducted in high-income
obesity 12955 dose-dependent positive association between diet soda consumption and BMI z-score, percent body fat, and odds of obesity in girls [[28]].Most recently, using data from the 2009–2014 US National Health and Nutrition Examination
obesity 13164 Examination Survey (NHANES), Sylvetsky et al. reported positive associations between NNS consumption and obesity . In adolescents (ages 12–19), odds of obesity were consistently higher in NNS consumers than non-consumers,
obesity 13212 reported positive associations between NNS consumption and obesity. In adolescents (ages 12–19), odds of obesity were consistently higher in NNS consumers than non-consumers, while in children (ages 2–11) this association
obesity 13824 consumption patterns in children, and identify potentially concerning associations with body composition and obesity . However, it must be acknowledged that confounding by reverse causation is possible in these cross-sectional
obesity 14296 Obesity-Related Outcomes in OffspringFew studies have investigated the effects of prenatal NNS exposure on obesity -related outcomes in offspring (Table 2). Two recent studies in Canada [[49]] and Denmark [[29]] have
obesity 15696 z-score at 7 years of age (adjusted 95% CI: 0.23, 0.96) and a 1.9-fold increased risk of overweight/ obesity (adjusted relative risk 1.93; 95% CI; 1.24, 3.01); however, in contrast to the CHILD cohort, no association
obesity 17717 birthweight. Overall, there is very little evidence regarding the effect of NNS consumption in pregnancy on obesity -related outcomes in offspring, and studies with different designs and analytical approaches have reached
obesity 22248 development of adipose tissue in the fetus [[63],[64]]. Routine NNS consumption has been associated with obesity -related impairments in glucose tolerance and energy homeostasis [[19],[65],[66]], which, when experienced
obesity 22431 [[19],[65],[66]], which, when experienced during pregnancy, are consistently associated with increased odds of obesity among offspring [[64],[65],[67]]. Thus, regular NNS intake during pregnancy may program an adverse metabolic
obesity 24236 in rodents, leading to impairments in glucose tolerance and the development of metabolic changes and obesity [[77],[78]].7. Limitations of Existing Studies and Knowledge Gaps Requiring Further ResearchIt is difficult
obesity 27180 cross-sectional study [[28]] and two RCTs [[31],[34]] have examined the relationship between NNS and childhood obesity outside of the US, Canada, or the UK. Therefore, it is unclear whether the reported findings are globally
obesity 28230 Expanding research efforts beyond high-income countries, particularly in areas with increasing rates of obesity and/or NNS consumption, should be prioritized to address the global impact of NNS. In addition, studies
obesity 29823 available.Figure 1Conceptual framework for the impact of early-life exposure to non-nutritive sweeteners (NNS) on obesity -related outcomes later in life. Potential causal mechanisms are shown in blue; potential confounding
obesity 30177 metabolism, taste preferences, and gut microbiota, ultimately influencing weight gain, adiposity and obesity .nutrients-10-00194-t001_Table 1Table 1Summary of human studies evaluating non-nutritive sweetener (NNS)
obesity 30319 1Table 1Summary of human studies evaluating non-nutritive sweetener (NNS) exposure during childhood and obesity -related outcomes.ReferenceSetting, Year, Study NameStudy PopulationAge at BaselineDuration of Follow
obesity 32842 servings/day, Youth FFQBaseline BMI, total energy intake, physical activity, puberty, age, sex, raceBMI, obesity No association with obesityNewby et al., 2004 [[37]]USA, 1995, ND WIC1345 children2–5 years6–12 monthsDiet
obesity 32869 BMI, total energy intake, physical activity, puberty, age, sex, raceBMI, obesityNo association with obesity Newby et al., 2004 [[37]]USA, 1995, ND WIC1345 children2–5 years6–12 monthsDiet soda, ounces/day,
obesity 34420 unspecified177 children3–6 years3 yearsASB, servings, 3-day food recordBaseline BMI, total energy intake, obesity risk status based on maternal BMIBMI z-score, waist circumferenceNo association of change in ASB consumption
obesity 36261 number per week, FFQAge, sex, study site, parent education, physical activityBMI z-score, % body fat, obesity Positive dose-dependent association of diet soda intake with BMI, % body fat and odds of obesity in girlsSylvetsky
obesity 36357 fat, obesityPositive dose-dependent association of diet soda intake with BMI, % body fat and odds of obesity in girlsSylvetsky et al. 2017 [[48]]USA, 2009–2014, NHANES9261 children and adolescents2–19 years-Foods
obesity 36620 24-h dietary recallsSex, race, family income, energy intake, physical activityObesityHigher odds of obesity in boys consuming ASB and Hispanic participants consuming NNS. Higher odds of obesity with NNS consumption
obesity 36706 activityObesityHigher odds of obesity in boys consuming ASB and Hispanic participants consuming NNS. Higher odds of obesity with NNS consumption in adolescents.Studies sorted by year of publication. Abbreviations: ALSPAC, Avon
obesity 37848 at the final assessment. Bold text indicates main direction of association between NNS exposure and obesity -related outcome.nutrients-10-00194-t002_Table 2Table 2Summary of human studies evaluating non-nutritive
obesity 38006 2Table 2Summary of human studies evaluating non-nutritive sweetener (NNS) exposure during pregnancy and obesity -related outcomes in offspring.Study, YearSetting, Year of Study Enrollment/Baseline Intake, Study NamenTiming
obesity 40259 child ASB/SSB consumption, physical activityLarge-for-gestational age (LGA), BMI z-score, overweight/ obesity Higher BMI and risk of LGA and overweight with daily maternal ASB intake (effect larger in boys)Studies
obesity 40830 sugar-sweetened beverage. Bold text indicates main direction of association between NNS exposure and obesity -related outcome.nutrients-10-00194-t003_Table 3Table 3Summary of animal studies evaluating early-life
obesity 40983 3Table 3Summary of animal studies evaluating early-life non-nutritive sweetener (NNS) exposure and obesity -related outcomes.Study, YearAnimal ModelNNS TypeNNS Dose, Route (Exposure) * to DamsTiming of NNS ExposureOutcomes
obesity 43776 consumption and body weight. Bold text indicates main direction of association between NNS exposure and obesity -related outcomes

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