Exposure to gestational diabetes mellitus in utero impacts hippocampal functional connectivity in response to food cues in children.

OBJECTIVES: Intrauterine exposure to gestational diabetes mellitus (GDM) increases the risk of obesity in the offspring, but little is known about the underlying neural mechanisms. The hippocampus is crucial for food intake regulation and is vulnerable to the effects of obesity. The purpose of the study was to investigate whether GDM exposure affects hippocampal functional connectivity during exposure to food cues using functional magnetic resonance imaging (fMRI). METHODS: Participants were 90 children age 7-11 years (53 females) who underwent an fMRI-based visual food cue task in the fasted state. Hippocampal functional connectivity (FC) was examined using generalized psychophysiological interaction in response to food versus non-food cues. Hippocampal FC was compared between children with and without GDM exposure, while controlling for possible confounding effects of age, sex and waist-to-hip ratio. In addition, the influence of childhood and maternal obesity were investigated using multiple regression models. RESULTS: While viewing high caloric food cues compared to non-food cure, children with GDM exposure exhibited higher hippocampal FC to the insula and striatum (i.e., putamen, pallidum and nucleus accumbens) compared to unexposed children. With increasing BMI, children with GDM exposure had lower hippocampal FC to the somatosensory cortex (i.e., postcentral gyrus). CONCLUSIONS: Intrauterine exposure to GDM was associated with higher food-cue induced hippocampal FC especially to reward processing regions. Future studies with longitudinal measurements are needed to clarify whether altered hippocampal FC may raise the risk of the development of metabolic diseases later in life.

Child physical activity as a modifier of the relationship between prenatal exposure to maternal overweight/obesity and neurocognitive outcomes in offspring.

BACKGROUND/OBJECTIVES: With rising obesity rates among pregnant women, more children are exposed in utero to maternal obesity. In prior epidemiological studies, exposure to maternal obesity was associated with lower intelligence quotient (IQ) scores and worse cognitive abilities in offspring. Further studies have shown that offspring exposed to maternal obesity, exhibit differences in the white matter microstructure properties, fractional anisotropy (FA) and mean diffusivity (MD). In contrast, physical activity was shown to improve cognition and white matter microstructure during childhood. We examined if child physical activity levels modify the relationship between prenatal exposure to maternal obesity with IQ and white matter microstructure in offspring. SUBJECTS/METHODS: One hundred children (59% girls) age 7-11 years underwent brain magnetic resonance imaging and IQ testing. Maternal pre-pregnancy BMI was abstracted from electronic medical records. White matter was assessed using diffusion tensor imaging with the measures, global FA, MD. The 3-day physical activity recall was used to measure moderate-to-vigorous physical activity and vigorous physical activity (VPA). Linear regression was used to test for interactions between prenatal exposure to maternal overweight/obesity and child PA levels on child IQ and global FA/MD. RESULTS: The relationship between prenatal exposure to maternal overweight/obesity and child IQ and global FA varied by child VPA levels. Children exposed to mothers with overweight/obesity who engaged in more VPA had higher IQ scores and global FA compared to exposed children who engaged in less VPA. Associations were independent of child age, sex, BMI Z-score and socioeconomic status. Children born to normal-weight mothers did not differ in either IQ or global FA by time in VPA. CONCLUSIONS: Our findings support findings in rodent models and suggest that VPA during childhood modifies the relationship between prenatal exposure to maternal obesity and child IQ and white matter microstructure.

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.

Exposure to gestational diabetes mellitus in utero impacts hippocampal functional connectivity in response to food cues in children.

Objectives: Intrauterine exposure to gestational diabetes mellitus (GDM) increases the risk of obesity in the offspring, but little is known about the underlying neural mechanisms. The hippocampus is crucial for food intake regulation and is vulnerable to the effects of obesity. The purpose of the study was to investigate whether GDM exposure affects hippocampal functional connectivity during exposure to food cues using functional magnetic resonance imaging. Methods: Participants were 90 children age 7-11 years (53 females) who underwent an fMRI-based visual food cue task in the fasted state. Hippocampal functional connectivity (FC) was examined using generalized psychophysiological interaction in response to high-calorie food versus non-food cues. Food-cue induced hippocampal FC was compared between children with and without GDM exposure, while controlling for possible confounding effects of age, sex and waist-to-hip ratio. Results: Children with GDM exposure exhibited stronger hippocampal FC to the insula and striatum (i.e., putamen, pallidum and nucleus accumbens) compared to unexposed children, while viewing high caloric food cues. Conclusions: Intrauterine exposure to GDM was associated with higher food-cue induced hippocampal FC to reward processing regions. Future studies with longitudinal measurements are needed to clarify whether increased hippocampal FC to reward processing regions may raise the risk of the development of metabolic diseases later in life.

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.

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.

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.

Associations Between Sleep and Metabolic Outcomes in Preadolescent Children.

Context: Growing evidence suggests an important role for sleep for the metabolic health of children. Objective: We aimed to determine how sleep is related to insulin sensitivity, insulin secretion, beta-cell function, and adiposity (BMI z-scores, body fat %, waist to height ratio) using objectively measured sleep and oral glucose tolerance test (OGTT)-derived measures. Methods: Sixty-two children aged 7-11 years, born at Kaiser Permanente Southern California, wore wrist accelerometers for 7 days to objectively measure sleep, completed an OGTT, and had anthropometric measures (height [cm], weight [kg], waist [cm], body fat [%]) collected. Using linear regression, associations between Matsuda insulin sensitivity index (ISI), insulinogenic index (IGI), disposition index (DI), BMI z-score, waist to height ratio, and body fat % with sleep parameters [total sleep time (TST; min), sleep efficiency (SE; %), time in bed (TIB; min), wake after sleep onset (WASO; min), and sleep latency (SL; min)] were assessed. Body fat % was tested as a mediator of the relationship between TST and ISI. Results: Longer TST was associated with better insulin sensitivity (P = 0.02), but not after adjusting for body fat %. Sleep parameters were not associated with IGI or DI. Longer TST was associated with lower % body fat (P = 0.01) and lower waist-to-height-ratios (P = 0.05). Body fat % explained 62% (P = 0.01) of the relationship between TST and ISI. Longer TIB was associated with lower adiposity measures (P < 0.05). There were no associations between SE, WASO, or SL and metabolic outcomes. Conclusion: Objectively measured sleep duration was associated with lower adiposity, and the relationship between sleep duration and ISI appeared partly through adiposity levels in preadolescent children. Longer sleep duration may be important for metabolic health.

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.