Perceived stress and associations between physical activity, sedentary time, and interstitial glucose in healthy adolescents.

BACKGROUND: Less moderate to vigorous physical activity (MVPA), more sedentary time (ST), and higher perceived stress are related to type 2 diabetes mellitus (T2DM) occurrence, but observational evidence addressing the interaction of these factors is lacking in youth. This pilot study investigated momentary stress as a moderator in the acute associations of MVPA and ST with subsequent glucose in healthy adolescents. METHODS: Participants (N=15, Mage=13.1±1.0 years, 10 girls, 5 with overweight/obesity) simultaneously wore a continuous glucose monitor (CGM), thigh-mounted accelerometer, and reported momentary stress via random ecological momentary assessments (EMA; Time T) for 7-14 days. MVPA and ST (min) were calculated for 60- and 120-minute time windows before each EMA prompt (Time T-1). Mean CGM-measured interstitial glucose (mg/dL) was calculated after each prompt (Mmin=120.0±25.4; Time T+1). Multilevel models assessed whether within-subject MVPA and ST (Time T-1) predicted mean glucose (Time T+1), with momentary stress as a moderator (Time T). RESULTS: There were 513 time-matched EMA reports of stress, accelerometer, and CGM data. Momentary stress moderated the effects of MVPA 60 (ß=-0.22, p=.001) and 120 min (ß=-0.08, p=.02) before the prompt on subsequent glucose levels. When youth spent more time in MVPA than their average and when momentary stress was higher than their average, subsequent glucose was lower. Stress did not moderate associations of ST with glucose (p>.05). CONCLUSIONS: Higher momentary stress may interact with higher MVPA to lower subsequent glucose in youth. Accelerometers, EMA, and CGMs can be integrated in future studies to further understand these associations in free-living environments.

Associations between affect dynamics and eating regulation in daily life: a preliminary ecological momentary assessment study.

Disordered eating behaviors consistently associated with emotion regulation difficulties. However, most studies have focused on affect intensity without considering dynamic affective patterns. We examined these patterns in relation to daily overeating, loss of control eating (LOCE), dietary restraint, and food craving in young adults using ecological momentary assessment (EMA).Adults (N = 24) completed a 10-day EMA protocol during which they reported momentary affect and eating patterns. Generalized linear mixed-models examined each index in relation to eating variable.Higher PA instability (within-person) was associated with higher ratings of binge-eating symptoms (B = 0.15, SE = 0.06, p = 0.007). Lower NA differentiation (within-person) was associated with higher levels of food craving (B = -10.11, SE = 4.74, p = 0.033).Our results support previous findings suggesting that acute fluctuations in PA may increase risk of binge-eating symptoms. Further, inability to differentiate between momentary states of NA was associated with cravings. This study highlights the importance of examining multiple facets of NA and PA in relation to eating regulation.Trial registration: ClinicalTrials.gov identifier: NCT02945475.

Influence of insulin sensitivity on food cue evoked functional brain connectivity in children.

Objective: Insulin resistance during childhood is a risk factor for developing type 2 diabetes and other health problems later in life. Studies in adults have shown that insulin resistance affects regional and network activity in the brain which are vital for behavior, e.g. ingestion and metabolic control. To date, no study has investigated whether brain responses to food cues in children are associated with peripheral insulin sensitivity. Methods: We included 53 children (36 girls) between the age of 7-11 years, who underwent an oral Glucose Tolerance Test (oGTT) to estimate peripheral insulin sensitivity (ISI). Brain responses were measured using functional magnetic resonance imaging (fMRI) before and after glucose ingestion. We compared food-cue task-based activity and functional connectivity (FC) between children with low and high ISI, adjusted for age and BMIz. Results: Independent of prandial state (i.e., glucose ingestion), children with lower ISI showed higher FC between the anterior insula and caudate and lower FC between the posterior insula and mid temporal cortex than children with higher ISI. Sex differences were found based on prandial state and peripheral insulin sensitivity in the insular FC. No differences were found on whole-brain food-cue reactivity. Conclusions: Children with low peripheral insulin sensitivity showed differences in food cue evoked response particularly in insula functional connectivity. These differences might influence eating behavior and future risk of developing diabetes.

Maternal obesity and diabetes during pregnancy and early autism screening score at well-child visits in standard clinical practice.

LAY ABSTRACT: Early intervention and treatment can help reduce disability in children diagnosed with autism spectrum disorder. Screening for autism spectrum disorder in young children identifies those at increased likelihood of diagnosis who may need further support. Previous research has reported that exposure to maternal obesity and diabetes during pregnancy is associated with higher likelihood of autism spectrum disorder diagnosis in children. However, little is known about whether these maternal conditions are associated with how very young children score on autism spectrum disorder screening tools. This study examined associations between exposure to maternal obesity and diabetes during pregnancy and offspring scores on the Quantitative Checklist for Autism in Toddlers, an autism spectrum disorder screening questionnaire administered between 18-24 months at well-child visits. A higher score on the Quantitative Checklist for Autism in Toddlers suggests a higher likelihood of autism spectrum disorder; children with scores 3 or greater are referred to developmental pediatricians for evaluation. Our study found that children of mothers with obesity or diabetes during pregnancy had higher scores than children whose mothers did not have these conditions. Associations with maternal obesity and gestational diabetes diagnosed at or before 26 weeks of pregnancy were also present in children who did not have later autism spectrum disorder diagnoses, suggesting that exposure to these conditions during early pregnancy may be associated with a broad range of social and behavioral abilities. Identifying associations between maternal health conditions and early Quantitative Checklist for Autism in Toddlers screening scores could influence future screening and provision of support for children of mothers with these conditions.

Types of diabetes during pregnancy and risk of depression and anxiety in offspring from childhood to young adulthood.

AIMS: To assess maternal pre-existing type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM) during pregnancy and risk of depression and anxiety from childhood to young adulthood in offspring. MATERIALS AND METHODS: This birth cohort included singletons born during 1995-2015, followed using electronic medical records through 2020. Cox regression was used to estimate hazard ratio (HR) of depression or anxiety diagnosis during follow-up associated with in-utero exposure to maternal diabetes. RESULTS: Among 439 590 offspring, 29 891 (6.8%) had depression and 51 918 (11.8%) had anxiety. T1D, followed by T2D and GDM requiring antidiabetes medication were associated with risk of depression and anxiety in offspring. Compared with no diabetes during pregnancy, the adjusted HRs (95% confidence interval) of depression in offspring associated with T1D, T2D or GDM requiring medications were 1.44 (1.09-1.91), 1.30 (1.15-1.47) and 1.18 (1.11-1.26) respectively; conversely, HRs were 0.97 (0.82-1.15) for T2D and 0.99 (0.94-1.04) for GDM without medications. The associations with anxiety followed similar patterns. The significant associations were observed for offspring ages 5-12 and >12-18 years and attenuated for 18-25 years. CONCLUSION: These data suggest that the severity of diabetes (T1D vs. T2D requiring medications vs. GDM requiring medications) during pregnancy may increase the vulnerability of offspring for depression or anxiety.

Associations among prenatal exposure to gestational diabetes mellitus, brain structure, and child adiposity markers.

OBJECTIVE: The aim of this study was to investigate the mediating role of child brain structure in the relationship between prenatal gestational diabetes mellitus (GDM) exposure and child adiposity. METHODS: This was a cross-sectional study of 9- to 10-year-old participants and siblings across the US. Data were obtained from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study®. Brain structure was evaluated by magnetic resonance imaging. GDM exposure was self-reported, and discordance for GDM exposure within biological siblings was identified. Mixed effects and mediation models were used to examine associations among prenatal GDM exposure, brain structure, and adiposity markers with sociodemographic covariates. RESULTS: The sample included 8521 children (7% GDM-exposed), among whom there were 28 sibling pairs discordant for GDM exposure. Across the entire study sample, prenatal exposure to GDM was associated with lower global and regional cortical gray matter volume (GMV) in the bilateral rostral middle frontal gyrus and superior temporal gyrus. GDM-exposed siblings also demonstrated lower global cortical GMV than unexposed siblings. Global cortical GMV partially mediated the associations between prenatal GDM exposure and child adiposity markers. CONCLUSIONS: The results identify brain markers of prenatal GDM exposure and suggest that low cortical GMV may explain increased obesity risk for offspring prenatally exposed to GDM.

Prenatal Exposure to Gestational Diabetes Mellitus is Associated with Mental Health Outcomes and Physical Activity has a Modifying Role.

Background: Studies suggest a link between prenatal gestational diabetes mellitus (GDM) exposure and poor mental health outcomes. We examined associations between prenatal GDM exposure and depressive and anxiety symptoms in children and assessed physical activity as a potential modifier of these associations. Method: Seventy children (AgeM(SD): 12(2.0), 56% GDM, 59% female) and their parents completed surveys: Center for Epidemiological Studies Depression Scale for Children (CES-DC), State-Trait Anxiety Inventory for Children (STAIC), Child Behavior Checklist (CBCL), and 3-day physical activity recall (3DPAR). Associations between mental health measures with GDM exposure and interactions between GDM exposure and child moderate-to-vigorous physical activity (MVPA) were assessed using regression. Results: GDM-exposed children had higher anxiety (p = 0.03) and internalizing symptoms (CBCL) (p = 0.04) than unexposed children. There was an interaction between GDM exposure and child MVPA on anxiety (p = 0.02), internalizing (p = 0.04) and externalizing symptoms (p = 0.004). In the low MVPA group, GDM exposed children had more depressive (p = 0.03), anxiety (p = 0.003), and internalizing symptoms (p = 0.03) than unexposed children. In the high MVPA group, there were no group differences except with externalizing symptoms (p = 0.04). Conclusion: Prenatal GDM is associated with higher anxiety and internalizing symptoms in children. Child MVPA modified the relationship between GDM exposure and mental health outcomes suggesting that physical activity during childhood could mitigate the negative mental health outcomes associated with prenatal GDM exposure.

Sweet taste preference is associated with greater hypothalamic response to glucose and longitudinal weight gain.

The hypothalamus has an abundant expression of sweet taste receptors that play a role in glucose sensing and energy homeostasis. Evidence suggests that liking "sweets" can be associated with weight gain, but the relationship between sweet taste preference and hypothalamic regulation of appetite is unknown. This study tested the hypothesis that sweet taste preference is associated with increased hypothalamic activation in response to glucose (a purported neural marker for weight gain risk) and greater longitudinal increases in body mass index (BMI). Fifty-four adults aged 18-35 years with a mean (± SD) BMI of 27.99 ± 5.32 kg/m2 completed the study. Height and weight were measured at baseline and 6-12 months later in a subset of 36 participants. Sweet taste preference was assessed via the Monell 2-series, forced-choice tracking procedure. Arterial spin labeling magnetic resonance imaging was performed before and after oral glucose ingestion to determine hypothalamic blood flow response to glucose. Linear models were used to examine relationships between sweet taste preference and the hypothalamic response to glucose and longitudinal changes in BMI, adjusting for age, sex, and baseline BMI. Sweet taste preference was positively associated with glucose-linked hypothalamic blood flow (beta = 0.017, p = 0.043), adjusted for age, sex and BMI. We also observed a positive association between sweet taste preference and longitudinal change in BMI (beta = 0.088, p = 0.015), adjusted for age, sex and baseline BMI. These findings suggest that heightened sweet taste preference is associated with glucose-linked hypothalamic activation and may be linked to increased susceptibility for weight gain.

Relationships between physical activity, healthy eating and cortical thickness in children and young adults.

Prior neuroimaging studies have shown associations between healthy lifestyle factors and cortical thickness; however, results on the direction of this association have been inconsistent. While the majority of studies were performed in older adults within specific weight status categories, little has been reported in younger populations with a range of adiposity, including groups with healthy-weight, overweight, and obesity. Here we investigated relationships between indices of physical activity (PA) and healthy eating with cortical thickness in children and youth/young adults and examined whether these relationships differed by weight status and age groups. Study participants included 119 youth/young adults and 159 children. We hypothesized that greater levels of PA and/or healthy eating index (HEI) composite scores would be positively associated with cortical thickness, and that this association would differ in overweight or obese groups versus normal weight groups, as well as youth/young adults vs. child cohorts. Overall PA (minutes/day) was assessed using 24-hour PA recalls. HEI was calculated to assess diet quality. A structural MRI was performed, and FreeSurfer 6.0 was used to assess cortical thickness in 68 regions of interest (ROI). Mixed effects modeling was performed to investigate associations of PA or HEI with cortical thickness. FDR corrections were applied for multiple ROIs. PA was positively associated with cortical thickness in the caudal middle frontal cortex (FDR adjusted p = 0.042) and cuneus cortex (FDR adjusted p = 0.017) after controlling for sex, age group, and weight status. When stratified by age, in youth/young adults, higher time spent in PA was associated with greater cortical thickness in the frontal, temporal, parietal and occipital cortex, after adjusting for sex and weight group (FDR adjusted ps < 0.05). No significant associations between PA and cortical thickness were observed in children. No significant associations between PA and cortical thickness were observed when stratified by weight group. No significant associations between HEI and cortical thickness were observed. These results indicate that higher time spent in PA is associated with greater cortical thickness, a relationship that appears to be stronger during youth/young adulthood and may be related to more favorable brain health outcomes.

Glucose variability: A physiological correlate of eating disorder behaviors among individuals with binge-spectrum eating disorders.

OBJECTIVES: Elevated glucose variability may be one mechanism that increases risk for significant psychological and physiological health conditions among individuals with binge-spectrum eating disorders (B-EDs), given the impact of eating disorder (ED) behaviors on blood glucose levels. This study aimed to characterize glucose variability among individuals with B-EDs compared with age-matched, sex-matched, and body mass index-matched controls, and investigate the association between frequency of ED behaviors and glucose variability. METHODS: Participants were 52 individuals with B-EDs and 22 controls who wore continuous glucose monitors to measure blood glucose levels and completed ecological momentary assessment surveys to measure ED behaviors for 1 week. Independent samples t-tests compared individuals with B-EDs and controls and multiple linear regression models examined the association between ED behaviors and glucose variability. RESULTS: Individuals with B-EDs demonstrated numerically higher glucose variability than controls (t = 1.42, p = .08, d = 0.43), although this difference was not statistically significant. When controlling for covariates, frequency of ED behaviors was significantly, positively associated with glucose variability (t = 3.17, p = .003) with medium effect size (f2  = 0.25). Post hoc analyses indicated that binge eating frequency was significantly associated with glucose variability, while episodes of 5+ hours without eating were not. DISCUSSION: Glucose variability among individuals with B-EDs appears to be positively associated with engagement in ED behaviors, particularly binge eating. Glucose variability may be an important mechanism by which adverse health outcomes occur at elevated rates in B-EDs and warrants future study. PUBLIC SIGNIFICANCE: This study suggests that some individuals with binge ED and bulimia nervosa may experience elevated glucose variability, a physiological symptom that is linked to a number of adverse health consequences. The degree of elevation in glucose variability is positive associated with frequency of eating disorder behaviors, especially binge eating.

Exposure to Gestational Diabetes Mellitus Prior to 26 Weeks Is Related to the Presence of Mediobasal Hypothalamic Gliosis in Children.

Intrauterine exposure to metabolic dysfunction leads to offspring metabolic dysfunction in human and rodent models, but underlying mechanisms are unclear. The mediobasal hypothalamus (MBH) is involved in energy homeostasis and weight regulation, and MBH gliosis is associated with obesity and insulin resistance. We tested the hypothesis that offspring exposed to gestational diabetes mellitus (GDM) in utero versus those unexposed would show evidence of MBH gliosis. Participants in the BrainChild Study (age 7-11 years with confirmed GDM exposure or no GDM exposure) underwent brain MRI to acquire T2-weighted images. By using the amygdala (AMY) and white matter (WM) as reference regions, MBH:AMY and MBH:WM T2 signal ratios were calculated as a radiologic measure of MBH gliosis. Linear regressions were used to examine associations between GDM exposure (GDM overall) and by timing of GDM exposure (≤26 weeks or >26 weeks) and MBH gliosis. Associations between prepregnancy BMI and child MBH gliosis were examined in secondary analyses. There were no differences in T2 signal ratios in children exposed versus not exposed to GDM overall, but children exposed to early GDM (≤26 weeks of gestation) had higher MBH:WM signal ratios than those not exposed (ß = 0.147; SE 0.06; P = 0.03), adjusting for child's age, sex, and BMI z score and maternal prepregnancy BMI, whereas no associations were seen for the control ratio (AMY:WM). Prepregnancy BMI was not associated with evidence of MBH gliosis. Early exposure to GDM was associated with radiologic evidence of MBH gliosis in children. These data provide mechanistic insight into brain pathways by which exposure to GDM may increase risk for metabolic dysfunction.

A gut reaction: Microbiome-driven glycemic effects of non-nutritive sweeteners.

Non-nutritive sweeteners are increasingly consumed to satisfy cravings for sweet taste without the associated calories. Paradoxically, non-nutritive sweeteners have been linked to metabolic risks, but the underlying mechanisms are not understood. In this issue of Cell, Suez and colleagues pinpoint changes in the gut microbiome as a mechanism for non-nutritive sweetener-induced glycemic impairments in healthy adults.

Time-Varying Associations Between Device-Based and Ecological Momentary Assessment-Reported Sedentary Behaviors and the Concurrent Affective States Among Adolescents: Proof-of-Concept Study.

BACKGROUND: Previous studies on affective state-sedentary behavior (SB) associations have not accounted for their potentially time-varying nature and have used inconsistent SB measurement modalities. We investigated whether the strength of the associations between affective states and SB varied as a function of the time of day and by SB measurement modality (device-measured SB vs ecological momentary assessment-reported screen-based SB) in youth. OBJECTIVE: This study aimed to establish a proof of concept that SB-affective state associations may not be static during the day. In addition, we aimed to inform the methodology of future work, which may need to model associations as functions of the time of day and carefully consider how SB is operationalized or measured. METHODS: A total of 15 adolescents (age: mean 13.07, SD 1.03 years; 10/15, 67% female; 6/15, 40% Hispanic; 10/15, 67% healthy weight) wore thigh-mounted activPAL accelerometers and simultaneously reported their screen-based SBs and concurrent positive and negative affective states via ecological momentary assessment for 7 to 14 days (N=636 occasions). Time-varying effect models (varying slopes) examined how each measure of SB was associated with concurrent affective states from 7 AM to 8 PM. RESULTS: Time-varying effect model plots revealed that these associations varied in strength throughout the day. Specifically, device-based SB was related to greater concurrent negative affect only after approximately 5 PM and was unrelated to concurrent positive affect. Screen-based SB was related to greater concurrent negative affect only from 7 AM to approximately 9 AM. This was also related to greater concurrent positive affect from 7 AM to approximately 9:30 AM and from approximately 3 PM to approximately 7 PM. CONCLUSIONS: We provide preliminary evidence to suggest that future confirmatory studies investigating the SB-affective state relationship should consider the time-varying nature of these associations and SB measurement modality. There may be critical time windows when specific types of SBs co-occur with affect, suggesting that interventions may need tailoring to the time of day and type of SB if future studies using similar methodologies can replicate our findings.

FGF21 response to sucrose is associated with BMI and dorsal striatal signaling in humans.

OBJECTIVE: This study examined associations between BMI and dietary sugar intake with sucrose-induced fibroblast growth factor 21 (FGF21) and whether circulating FGF21 is associated with brain signaling following sucrose ingestion in humans. METHODS: A total of 68 adults (29 male; mean [SD), age 23.2 [3.8] years; BMI 27.1 [4.9] kg/m2 ) attended visits after a 12-hour fast. Plasma FGF21 was measured at baseline and at 15, 30, and 120 minutes after sucrose ingestion (75 g in 300 mL of water). Brain cerebral blood flow responses to sucrose were measured using arterial spin labeling magnetic resonance imaging. RESULTS: Higher circulating FGF21 levels were associated with reduced blood flow in the striatum in response to sucrose (ß = -7.63, p = 0.03). This association was greatest among persons with healthy weight (ß = -15.70, p = 0.007) and was attenuated in people with overweight (ß = -4.00, p = 0.63) and obesity (ß = -12.45, p = 0.13). BMI was positively associated with FGF21 levels in response to sucrose (ß = 0.53, p = 0.02). High versus low dietary sugar intake was associated with greater FGF21 responses to acute sucrose ingestion in individuals with healthy weight (ß = 8.51, p = 0.04) but not in individuals with overweight or obesity (p > 0.05). CONCLUSIONS: These correlative findings support evidence in animals showing that FGF21 acts on the brain to regulate sugar consumption through a negative feedback loop.

Patterns of Objectively Measured Sedentary Time and Emotional Disorder Symptoms Among Youth.

OBJECTIVE: We examined the within-person longitudinal and bidirectional associations between patterns of sedentary time accumulation [alpha (sedentary bout duration/length), sedentary breaks (number of breaks in sedentary bouts)], and symptoms of major depressive disorder and generalized anxiety disorder. METHODS: Children [N = 167, 10.1(0.9) years old, 54.5% female, 59.3% Hispanic, 35.9% overweight/obese at baseline] participated in a 3-year longitudinal study that consisted of assessments of sedentary time, and depressive and anxiety symptoms. At each assessment, participants wore accelerometers and completed the Revised Child Anxiety and Depression Scale. Separate random intercept cross-lagged panel models estimated the within-person longitudinal and bidirectional associations between alpha, sedentary breaks, and symptoms of major depressive disorder and generalized anxiety disorder across chronological age intervals. RESULTS: Having greater than one's own usual depressive symptoms at age 11 was associated with fewer sedentary breaks 1 year later. Having greater than one's own usual generalized anxiety symptoms at age 11 was associated with longer sedentary bouts and fewer sedentary breaks 1 year later. In contrast, having greater than one's own usual sedentary breaks at age 10 was associated with fewer generalized anxiety symptoms 1 year later. All other associations, including at younger ages, were null. CONCLUSION: Deviations from one's usual levels of depressive or anxiety symptoms may be important for how sedentary time is subsequently accumulated. Intraindividual processes appear to be at play, therefore more within-person research is needed. Intervention strategies for promoting a healthier accumulation of sedentary time may consider targeting occasions when depressive and anxiety symptoms are greater than usual.

Brain responses to glucose ingestion are greater in children than adults and are associated with overweight and obesity.

OBJECTIVE: This study investigated whether brain regions involved in the regulation of food intake respond differently to glucose ingestion in children and adults and the relationship between brain responses and weight status. METHODS: Data included 87 children (ages 7-11 years) and 94 adults (ages 18-35 years) from two cohorts. Healthy weight, overweight, and obesity were defined by Centers for Disease Control and Prevention criteria. Brain responses to glucose were determined by measuring cerebral blood flow using arterial spin labeling magnetic resonance imaging in brain regions involved in the regulation of eating behavior. RESULTS: Children showed significantly larger increases in brain responses to glucose than adults in the dorsal striatum (p < 0.01), insula (p < 0.01), hippocampus (p < 0.01), and dorsal-lateral prefrontal cortex (p < 0.01). Responses to glucose in the dorsal striatum (odds ratio [OR] = 1.52, 95% CI 1.05-2.20; p = 0.03), hippocampus (OR = 1.51, 95% CI: 1.02-2.22; p = 0.04), insula (OR = 1.64, 95% CI: 1.11-2.42; p = 0.01), and orbitofrontal cortex (OR = 1.63 95% CI: 1.12-2.39; p = 0.01) were positively associated with overweight or obesity, independent of age group. CONCLUSIONS: Children have greater brain responses to glucose ingestion than adults in regions involved in eating behavior, and these responses are associated with weight status.

Obesity and Sex-Related Associations With Differential Effects of Sucralose vs Sucrose on Appetite and Reward Processing: A Randomized Crossover Trial.

Importance: Nonnutritive sweeteners (NNSs) are used as an alternative to nutritive sweeteners to quench desire for sweets while reducing caloric intake. However, studies have shown mixed results concerning the effects of NNSs on appetite, and the associations between sex and obesity with reward and appetitive responses to NNS compared with nutritive sugar are unknown. Objective: To examine neural reactivity to different types of high-calorie food cues (ie, sweet and savory), metabolic responses, and eating behavior following consumption of sucralose (NNS) vs sucrose (nutritive sugar) among healthy young adults. Design, Setting, and Participants: In a randomized, within-participant, crossover trial including 3 separate visits, participants underwent a functional magnetic resonance imaging task measuring blood oxygen level-dependent signal in response to visual cues. For each study visit, participants arrived at the Dornsife Cognitive Neuroimaging Center of University of Southern California at approximately 8:00 am after a 12-hour overnight fast. Blood was sampled at baseline and 10, 35, and 120 minutes after participants received a drink containing sucrose, sucralose, or water to measure plasma glucose, insulin, glucagon-like peptide(7-36), acyl-ghrelin, total peptide YY, and leptin. Participants were then presented with an ad libitum meal. Participants were right-handed, nonsmokers, weight-stable for at least 3 months before the study visits, nondieters, not taking medication, and with no history of eating disorders, illicit drug use, or medical diagnoses. Data analysis was performed from March 2020 to March 2021. Interventions: Participants ingested 300-mL drinks containing either sucrose (75 g), sucralose (individually sweetness matched), or water (as a control). Main Outcomes and Measures: Primary outcomes of interest were the effects of body mass index (BMI) status and sex on blood oxygen level-dependent signal to high-calorie food cues, endocrine, and feeding responses following sucralose vs sucrose consumption. Secondary outcomes included neural, endocrine, and feeding responses following sucrose vs water and sucralose vs water (control) consumption, and cue-induced appetite ratings following sucralose vs sucrose (and vs water). Results: A total of 76 participants were randomized, but 2 dropped out, leaving 74 adults (43 women [58%]; mean [SD] age, 23.40 [3.96] years; BMI range, 19.18-40.27) who completed the study. In this crossover design, 73 participants each received water (drink 1) and sucrose (drink 2), and 72 participants received water (drink 1), sucrose (drink 2), and sucralose (drink 3). Sucrose vs sucralose was associated with greater production of circulating glucose, insulin, and glucagon-like peptide-1 and suppression of acyl-ghrelin, but no differences were found for peptide YY or leptin. BMI status by drink interactions were observed in the medial frontal cortex (MFC; P for interaction < .001) and orbitofrontal cortex (OFC; P for interaction = .002). Individuals with obesity (MFC, ß, 0.60; 95% CI, 0.38 to 0.83; P < .001; OFC, ß, 0.27; 95% CI, 0.11 to 0.43; P = .002), but not those with overweight (MFC, ß, 0.02; 95% CI, -0.19 to 0.23; P = .87; OFC, ß, -0.06; 95% CI, -0.21 to 0.09; P = .41) or healthy weight (MFC, ß, -0.13; 95% CI, -0.34 to 0.07; P = .21; OFC, ß, -0.08; 95% CI, -0.23 to 0.06; P = .16), exhibited greater responsivity in the MFC and OFC to savory food cues after sucralose vs sucrose. Sex by drink interactions were observed in the MFC (P for interaction = .03) and OFC (P for interaction = .03) after consumption of sucralose vs sucrose. Female participants had greater MFC and OFC responses to food cues (MFC high-calorie vs low-calorie cues, ß, 0.21; 95% CI, 0.05 to 0.37; P = .01; MFC sweet vs nonfood cues, ß, 0.22; 95% CI, 0.02 to 0.42; P = .03; OFC food vs nonfood cues, ß, 0.12; 95% CI, 0.02 to 0.22; P = .03; and OFC sweet vs nonfood cues, ß, 0.15; 95% CI, 0.03 to 0.27; P = .01), but male participants' responses did not differ (MFC high-calorie vs low-calorie cues, ß, 0.01; 95% CI, -0.19 to 0.21; P = .90; MFC sweet vs nonfood cues, ß, -0.04; 95% CI, -0.26 to 0.18; P = .69; OFC food vs nonfood cues, ß, -0.08; 95% CI, -0.24 to 0.08; P = .32; OFC sweet vs nonfood cues, ß, -0.11; 95% CI, -0.31 to 0.09; P = .31). A sex by drink interaction on total calories consumed during the buffet meal was observed (P for interaction = .03). Female participants consumed greater total calories (ß, 1.73; 95% CI, 0.38 to 3.08; P = .01), whereas caloric intake did not differ in male participants (ß, 0.68; 95% CI, -0.99 to 2.35; P = .42) after sucralose vs sucrose ingestion. Conclusions and Relevance: These findings suggest that female individuals and those with obesity may be particularly sensitive to disparate neural responsivity elicited by sucralose compared with sucrose consumption. Trial Registration: ClinicalTrials.gov Identifier: NCT02945475.

Obesity and Dietary Added Sugar Interact to Affect Postprandial GLP-1 and Its Relationship to Striatal Responses to Food Cues and Feeding Behavior.

It has been hypothesized that the incretin hormone, glucagon-like peptide-1 (GLP-1), decreases overeating by influencing mesolimbic brain regions that process food-cues, including the dorsal striatum. We previously showed that habitual added sugar intake was associated with lower glucose-induced circulating GLP-1 and a greater striatal response to high calorie food cues in lean individuals. Less is known about how dietary added sugar and obesity may interact to affect postprandial GLP-1 and its relationship to striatal responses to food cues and feeding behavior. The current study aimed to expand upon previous research by assessing how circulating GLP-1 and striatal food cue reactivity are affected by acute glucose consumption in participants with varied BMIs and amounts of habitual consumption of added sugar. This analysis included 72 participants from the Brain Response to Sugar Study who completed two study visits where they consumed either plain water or 75g glucose dissolved in water (order randomized; both drinks were flavored with non-caloric cherry flavoring) and underwent repeated blood sampling, a functional magnetic resonance imaging (fMRI) based food-cue task, and an ad-libitum buffet meal. Correlations between circulating GLP-1 levels, striatal food-cue reactivity, and food intake were assessed, and interactions between obesity and added sugar on GLP-1 and striatal responses were examined. An interaction between BMI and dietary added sugar was associated with reduced post-glucose GLP-1 secretion. Participants who were obese and consumed high levels of added sugar had the smallest increase in plasma GLP-1 levels. Glucose-induced GLP-1 secretion was correlated with lower dorsal striatal reactivity to high-calorie versus low-calorie food-cues, driven by an increase in reactivity to low calorie food-cues. The increase in dorsal striatal reactivity to low calorie food-cues was negatively correlated with sugar consumed at the buffet. These findings suggest that an interaction between obesity and dietary added sugar intake is associated with additive reductions in postprandial GLP-1 secretion. Additionally, the results suggest that changes to dorsal striatal food cue reactivity through a combination of dietary added sugar and obesity may affect food consumption.

Associations Between Exposure to Gestational Diabetes Mellitus In Utero and Daily Energy Intake, Brain Responses to Food Cues, and Adiposity in Children.

OBJECTIVE: Children exposed to gestational diabetes mellitus (GDM) or maternal obesity in utero have an increased propensity to develop obesity. Little is known about the mechanisms underlying this phenomenon. We aimed to examine relationships between exposure to GDM or maternal obesity and daily energy intake (EI), brain responses to food cues within reward regions, and adiposity in children. RESEARCH DESIGN AND METHODS: Participants were 159 children ages 7-11 years. Repeated 24-h recalls were conducted to assess mean daily EI. A subset of children (n = 102) completed a food cue task in the MRI scanner. A priori regions of interest included the orbital frontal cortex (OFC), insula, amygdala, ventral striatum, and dorsal striatum. Adiposity measurements, BMI z-scores, percent body fat, waist-to-height ratio (WtHR), and waist-to-hip ratio (WHR) were assessed. RESULTS: Exposure to GDM was associated with greater daily EI, and children exposed to GDM diagnosed before 26 weeks gestation had greater OFC food cue reactivity. Children exposed to GDM also had larger WHR. Results remained significant after adjusting for child's age and sex, maternal education and race/ethnicity, maternal prepregnancy BMI, and child's physical activity levels. Furthermore, children who consumed more daily calories had greater WHR, and the relationship between GDM exposure and WHR was attenuated after adjustment for daily EI. Prepregnancy BMI was not significantly related to daily EI or food cue reactivity in reward regions. However, prepregnancy BMI was significantly related to all adiposity measurements; results remained significant for BMI z-scores, WtHR, and WHR after controlling for child's age and sex, maternal education and race/ethnicity, maternal GDM exposure, and child's physical activity levels. CONCLUSIONS: Exposure to GDM in utero, in particular before 26 weeks gestation, is associated with increased EI, enhanced OFC food cue reactivity, and increased WHR. Future study with longitudinal follow-up is merited to assess potential pathways of daily EI and food cue reactivity in reward regions on the associations between GDM exposure and childhood adiposity.