The ongoing obesity and type 2 diabetes epidemics have prompted recommendations to replace added sugar with artificial sweeteners (ArtSws) in foods and beverages. While ArtSws offer lower caloric content, growing evidence suggests potential adverse effects, including adipose tissue (AT) accumulation and obesity. Previous observational studies have linked ArtSw intake to higher BMI, waist circumference, and obesity risk. Experimental studies using cell cultures and animal models have also shown that ArtSws might have direct adipogenic effects, potentially through mechanisms like hyperphagia and altered intestinal enzyme activity. However, some studies have reported null findings, highlighting the need for further research. Critically, studies lacking long-term follow-up and control for diet quality and caloric intake are limited. This study aimed to address these gaps by examining the association between habitual, long-term ArtSw intake (aspartame, sucralose, saccharin) and diet beverage consumption with AT volumes (visceral, intermuscular, subcutaneous), anthropometric measures, and obesity incidence in the CARDIA cohort. The researchers hypothesized that higher intakes of ArtSws and diet beverages would be associated with greater AT volumes, irrespective of caloric intake and diet quality.

Existing literature on artificial sweeteners and their impact on body weight and composition presents a mixed picture. Meta-analyses of observational studies have generally shown a positive correlation between ArtSw intake and markers of adiposity, including increased waist circumference and BMI, and higher risk of obesity. These studies, however, often had limitations including shorter follow-up periods and less precise measures of sweetener intake. Experimental studies (cell cultures and animal models) have revealed potential mechanisms by which ArtSws may promote fat accumulation, such as influencing appetite (hyperphagia) or affecting intestinal enzyme activity impacting weight regulation. Conversely, some randomized controlled trials (RCTs) reported modest weight loss with ArtSw substitution for sugar, often attributed to controlled caloric intake within the trial context. The inconsistency across studies highlights the need for a long-term observational study that controls for confounding factors such as overall diet quality and energy intake, which this study aims to provide.

The Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective cohort study, provided the data for this analysis. 3088 participants (initially 5115) aged 18-30 years at baseline (1985-1986) were included after exclusions for missing data, implausible energy intake, missing CT scans, or other missing data. Participants were predominantly Black and White men and women from four US metropolitan areas. Data on demographic characteristics, lifestyle factors (physical activity, smoking, alcohol intake), and anthropometric measures (height, weight, BMI, waist circumference) were collected at baseline, year 7, and year 20. Dietary intake, including artificial sweetener consumption (aspartame, sucralose, saccharin), was assessed using a validated diet history questionnaire at the same time points. At year 25, computed tomography (CT) scans were used to measure volumes of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT). The Healthy Eating Index 2015 (HEI2015) was calculated to assess diet quality. Linear regression analyses evaluated the associations between ArtSw intake (quintiles for total ArtSw, aspartame, sucralose; tertiles for saccharin) and diet beverage intake (quintiles) with AT volumes, anthropometric measures, and 25-year changes in anthropometry. Cox regression analysis assessed the associations between ArtSw intake and incident obesity over a median 17.5-year follow-up. All analyses adjusted for age, sex, race, field center, education, height, smoking status, alcohol consumption, physical activity, energy intake, and HEI2015 score.

Higher intakes of total artificial sweeteners, aspartame, saccharin, and diet beverages were significantly associated with greater volumes of VAT, SAT, and IMAT (all p-trends ≤0.001). No significant associations were observed for sucralose intake. Increased ArtSw intake was also associated with higher BMI, body weight, and waist circumference at year 25, along with greater increases in these measures over the 25-year period. Except for saccharin (p-trend = 0.13), all ArtSw exposures, including diet soda, were significantly associated with a greater risk of incident obesity over the 17.5-year follow-up (all p-trends <0.05). Specifically, individuals in the highest quintile of total ArtSw, aspartame, and diet beverage intake had 78%, 64%, and 57% greater risks of incident obesity, respectively, compared to those in the lowest quintile. While saccharin showed a modest, but non-significant trend, individuals in the second and third tertiles displayed a 13% and 19% higher risk of incident obesity respectively. These associations remained significant after adjusting for age, sex, race, field center, education, height, smoking, alcohol consumption, physical activity, energy intake, and HEI2015 score.

This study provides strong evidence linking long-term consumption of aspartame, saccharin, and diet beverages to increased adipose tissue accumulation and obesity risk, independent of overall caloric intake and diet quality. The findings extend previous research by examining individual ArtSws and considering longer-term effects. The lack of association with sucralose warrants further investigation. While some RCTs have shown modest weight loss with ArtSw use, these studies often involve controlled settings and shorter timeframes, differing significantly from real-world consumption patterns. This study's longitudinal design and comprehensive assessment of diet and body composition provide compelling evidence supporting a potential link between certain ArtSws and adverse metabolic outcomes. Although the mechanism isn't fully elucidated, existing literature suggests potential pathways like hyperphagia and changes in gut microbiota and intestinal enzyme activity. This research contributes significantly to the ongoing debate on the health effects of artificial sweeteners.

This large, long-term observational study provides novel evidence for the association between habitual ArtSw intake and increased adipose tissue deposition and obesity risk. The findings challenge current recommendations advocating for the replacement of sugar with ArtSws. Future research should focus on elucidating the precise mechanisms involved, investigating the effects of newer ArtSws, and exploring the potential modifying roles of other dietary and lifestyle factors. The implications suggest a critical need for reconsidering the widespread recommendation to use artificial sweeteners in place of sugar.

Several limitations should be acknowledged. The reliance on self-reported dietary intake might introduce measurement error, although such error is likely to bias results toward the null. The study did not capture data on newer ArtSws such as stevia or advantame, limiting its generalizability. The potential for residual confounding, while minimized through multiple adjustments, cannot be entirely ruled out. Reverse causality, where individuals with higher BMI might consume more ArtSws, is also possible, but the long-term design of the study and the repeated measures of ArtSw intake reduce this possibility. Furthermore, the study did not assess the potential impact of ArtSw on the gut microbiome, which might also influence adipogenesis and metabolic health.