Hypothalamic Gliosis is Associated With Multiple Cardiovascular Disease Risk Factors.

Background: Hypothalamic gliosis is mechanistically linked to obesity and insulin resistance in rodent models. We tested cross-sectional associations between radiologic measures of hypothalamic gliosis in humans and clinically relevant cardiovascular disease risk factors, as well as prevalent coronary heart disease. Methods: Using brain MRI images from Framingham Heart Study participants (N=867; mean age, 55 years; 55% females), T2 signal intensities were extracted bilaterally from the region of interest in the mediobasal hypothalamus (MBH) and reference regions in the amygdala (AMY) and putamen (PUT). T2 signal ratios were created in which greater relative T2 signal intensity suggests gliosis. The primary measure compared MBH to AMY (MBH/AMY); a positive control ratio (MBH/PUT) also assessed MBH whereas a negative control (PUT/AMY) did not. Outcomes were BMI, HDL-C, LDL-C, fasting triglycerides, and the presence of hypertension (n=449), diabetes mellitus (n=66), metabolic syndrome (n=254), or coronary heart disease (n=25). Dietary risk factors for gliosis were assessed in a prospective analysis. Statistical testing was performed using linear or logistic regression. Results: Greater MBH/AMY T2 signal ratios were associated with higher BMI (ß = 21.5 [95% CI, 15.4-27.6]; P<0.001), higher fasting triglycerides (ß = 1.1 [95% CI, 0.6-1.7]; P<0.001), lower HDL-C (ß = -20.8 [95% CI, -40.0 to -1.6]; P=0.034), and presence of hypertension (odds ratio, 1.2 [95% CI, 1.1-1.4]; P=0.0088), and the latter two were independent of BMI. Findings for diabetes mellitus were mixed and attenuated by adjusting for BMI. Metabolic syndrome was associated with MBH/AMY T2 signal ratios (odds ratio, 1.3 [95% CI, 1.1-1.6]; P<0.001). Model results were almost uniformly confirmed by the positive control ratios, whereas negative control ratios that did not test the MBH were unrelated to any outcomes (all P≥0.05). T2 signal ratios were not associated with prevalent coronary heart disease (all P>0.05), but confidence intervals were wide. Self-reported percentages of macronutrient intake were not consistently related to future T2 signal ratios. Conclusions: Using a well-established study of cardiovascular disease development, we found evidence linking hypothalamic gliosis to multiple cardiovascular disease risk factors, even independent of adiposity. Our results highlight the need to consider neurologic mechanisms to understand and improve cardiometabolic health.

Genetic associations with neural reward responsivity to food cues in children.

Objective: To test associations of candidate obesity-related single nucleotide polymorphisms (SNPs) and obesity polygenic risk scores (PRS) with neural reward reactivity to food cues. Methods: After consuming a pre-load meal, 9-12-year-old children completed a functional magnetic resonance imaging (fMRI) paradigm with exposure to food and non-food commercials. Genetic exposures included FTO rs9939609, MC4R rs571312, and a pediatric-specific obesity PRS. A targeted region-of-interest (ROI) analysis for 7 bilateral reward regions and a whole-brain analysis were conducted. Independent associations between each genetic factor and reward responsivity to food cues in each ROI were evaluated using linear models. Results: Analyses included 151 children (M = 10.9 years). Each FTO rs9939609 obesity risk allele was related to a higher food-cue-related response in the right lateral hypothalamus after controlling for covariates including the current BMI Z-score (p < 0.01), however, the association did not remain significant after applying the multiple testing correction. MC4R rs571312 and the PRS were not related to heightened food-cue-related reward responsivity in any examined regions. The whole-brain analysis did not identify additional regions of food-cue-related response related to the examined genetic factors. Conclusion: Children genetically at risk for obesity, as indicated by the FTO genotype, may be predisposed to higher food-cue-related reward responsivity in the lateral hypothalamus in the sated state, which, in turn, could contribute to overconsumption. Clinical trial registration: https://clinicaltrials.gov/study/NCT03766191, identifier NCT03766191.

Genetic associations with consumption of palatable foods in the absence of hunger in response to food cues in children.

OBJECTIVE: The objective of this study is to evaluate obesity-related genetic factors in relation to excess consumption and assess if food cues modify associations. METHODS: Children (9-12 years) completed a randomized crossover experiment. During two visits, children ate a preload and then snacks ad libitum while watching television, embedded with food or non-food advertisements to assess eating in the absence of hunger (EAH). Primary exposures were obesity-associated genotypes, FTO rs9939609 and MC4R rs571312, and a paediatric-specific polygenic risk score (PRS). Outcomes included consumption of all snacks (total EAH) and gummy candy only (gummy candy EAH). Linear mixed-effects models tested whether genetic exposures related to EAH outcomes. We tested for effect modification by food cues using multiplicative interaction terms. RESULTS: Among 177 children, each FTO risk allele was associated with a 30% increase in gummy candy EAH (p = 0.025) in adjusted models. Food cue exposure exacerbated associations between the FTO variant with gummy candy EAH (p = 0.046). No statistically significant associations were found between MC4R and EAH. CONCLUSION: The results suggest children with the FTO rs9939609 risk allele may be predisposed to excess consumption of candy and that this association may be exacerbated by food cues.

The associations between attentional bias to food cues, parent-report appetitive traits, and concurrent adiposity among adolescents.

OBJECTIVE: To assess whether attentional bias to food cues and appetitive traits are independently and interactively associated with adiposity in adolescents. METHOD: Eighty-five adolescents, 14-17-years had their attentional bias to food images measured in a sated state by computing eye tracking measures of attention (first fixation duration, cumulative fixation duration) to food and control distractor images that bordered a computer game. Parents reported adolescent appetitive traits including the food approach domains of enjoyment of food, food responsiveness, emotional overeating, and the food avoidance domains of satiety responsiveness and emotional overeating through the Children's Eating Behavior Questionnaire. RESULTS: First fixation bias to food cues was positively associated with enjoyment of food, and negatively associated with satiety responsiveness. In a series of regression models adjusted for relevant covariates, first fixation bias to food cues (ß = 0.83, p = 0.007), higher food responsiveness (ß = 0.74, p < 0.001), higher emotional overeating (ß = 0.51, p = 0.002), and a composite appetite score (ß = 1.42, p < 0.001) were each significantly associated with greater BMI z-scores. In models assessing the interactive effects between attentional bias and appetitive traits, higher first fixation bias to food cues interacted synergistically with food responsiveness and emotional overeating in relation to BMI z-score. A synergistic interaction between first fixation bias to food cues and the composite appetite score in relation to BMI z-score was also observed. CONCLUSION: Individuals with high attentional bias to food cues and obesogenic appetitive traits may be particularly susceptible to weight gain.

Elucidating pathways to pediatric obesity: a study evaluating obesity polygenic risk scores related to appetitive traits in children.

BACKGROUND/OBJECTIVES: Obesity polygenic risk scores (PRS) explain substantial variation in body mass index (BMI), yet associations between PRSs and appetitive traits in children remain unclear. To better understand pathways leading to pediatric obesity, this study aimed to assess the association of obesity PRSs and appetitive traits. SUBJECTS/METHODS: This study included 248 unrelated children aged 9-12 years. DNA from the children was genotyped (236 met quality control thresholds) and four weighted polygenic risk scores from previous studies were computed and standardized: a 97 SNP PRS, 266 SNP pediatric-specific PRS, 466 SNP adult-specific PRS, and ~2 million SNP PRS. Appetitive traits were assessed using a parent-completed Child Eating Behavior Questionnaire, which evaluated food approach/avoidance traits and a composite obesogenic appetite score. BMI was directly measured and standardized by age and sex. Three associations were evaluated with linear regression: (1) appetitive traits and BMI, (2) PRSs and BMI, and (3) PRSs and appetitive traits, the primary association of interest. RESULTS: Expected positive associations were observed between obesogenic appetitive traits and BMI and all four PRSs and BMI. Examining the association between PRSs and appetitive traits, all PRSs except for the 466 SNP adult PRS were significantly associated with the obesogenic appetite score. Each standard deviation increase in the 266 SNP pediatric PRS was associated with an adjusted 2.1% increase in obesogenic appetite score (95% CI: 0.6%, 3.7%, p = 0.006). Significant partial mediation of the PRS-BMI association by obesogenic appetite score was found for these PRSs; for example, 21.3% of the association between the 266 SNP pediatric PRS and BMI was explained by the obesogenic appetite score. CONCLUSIONS: Genetic obesity risk significantly predicted appetitive traits, which partially mediated the association between genetic obesity risk and BMI in children. These findings build a clearer picture of pathways leading to pediatric obesity.

Associations between behavioral self-regulation and external food cue responsiveness (EFCR) in preschool-age children and evidence of modification by parenting style.

Decreased behavioral regulation is hypothesized to be a risk factor for excess weight gain among children, possibly via reduced appetite-specific regulation. Little research has specifically focused on behavioral regulation and food cue responsiveness, a conditioned precursor to eating, at a young age. This study examined the association between behavioral regulation and external food cue responsiveness among preschool-age children and explored if a more structured parenting style moderated that association. Baseline data from a prospective study on media use among preschool-age children (n = 83) in Northern New England were used. Parents reported on three domains of children's behavioral regulation (attentional focusing, inhibitory control, and emotional self-regulation), the children's external food cue responsiveness (EFCR), and their parenting styles (authoritative and permissive) via validated questionnaires. Mean age among children was 4.31 (SD 0.91) years, 57% of children were male, 89% were non-Hispanic white, and 26.2% had overweight or obesity. In a series of adjusted linear regression models, lower attentional focusing (standardized ß, ßs = -0.35, p = 0.001), inhibitory control (ßs = -0.30, p = 0.008), and emotional self-regulation (standardized beta, ßs = -0.38, p < 0.001) were each significantly associated with greater EFCR. In exploratory analyses, a more structured parenting style (more authoritative or less permissive) mitigated the associations between inhibitory control and EFCR (Bonferroni-adjusted p-interaction < 0.017). Findings support that lower attentional focusing, inhibitory control, and emotional self-regulation relate to greater ECFR in preschool-age children. The association between inhibitory control and EFCR may be modified by parenting style. Further research is needed to understand if children's responsiveness to external food cues may account for reported associations between lower behavioral regulation and adiposity gain over time.

Corrigendum: Differential neural reward reactivity in response to food advertising medium in children.

[This corrects the article DOI: 10.3389/fnins.2023.1052384.].

Differential neural reward reactivity in response to food advertising medium in children.

Introduction: Food cues including food advertisements (ads) activate brain regions related to motivation and reward. These responses are known to correlate with eating behaviors and future weight gain. The objective of this study was to compare brain responses to food ads by different types of ad mediums, dynamic (video) and static (images), to better understand how medium type impacts food cue response. Methods: Children aged 9-12 years old were recruited to complete a functional magnetic resonance imaging (fMRI) paradigm that included both food and non-food dynamic and static ads. Anatomical and functional images were preprocessed using the fMRIPrep pipeline. A whole-brain analysis and a targeted region-of-interest (ROI) analysis for reward regions (nucleus accumbens, orbitofrontal cortex, amygdala, insula, hypothalamus, ventral tegmental area, substantia nigra) were conducted. Individual neural responses to dynamic and static conditions were compared using a paired t-test. Linear mixed-effects models were then constructed to test the differential response by ad condition after controlling for age, sex, BMI-z, physical activity, and % of kcal consumed of a participant's estimated energy expenditure in the pre-load prior to the MRI scan. Results: A total of 115 children (mean=10.9 years) completed the fMRI paradigm. From the ROI analyses, the right and left hemispheres of the amygdala and insula, and the right hemisphere of the ventral tegmental area and substantia nigra showed significantly higher responses for the dynamic food ad medium after controlling for covariates and a false discovery rate correction. From the whole-brain analysis, 21 clusters showed significant differential responses between food ad medium including the precuneus, middle temporal gyrus, superior temporal gyrus, and inferior frontal gyrus, and all regions remained significant after controlling for covariates. Discussion: Advertising medium has unique effects on neural response to food cues. Further research is needed to understand how this differential activation by ad medium ultimately affects eating behaviors and weight outcomes.

Associations of maternal plasma and umbilical cord plasma metabolomics profiles with birth anthropometric measures.

BACKGROUND: The metabolomics profiles of maternal plasma during pregnancy and cord plasma at birth might influence fetal growth and birth anthropometry. The objective was to examine how maternal plasma and umbilical cord plasma metabolites are associated with newborn anthropometric measures, a known predictor of future health outcomes. METHODS: Pregnant women between 24 and 28 weeks of gestation were recruited as part of a prospective cohort study. Blood samples from 413 women at enrollment and 787 infant cord blood samples were analyzed using the Biocrates AbsoluteIDQ® p180 kit. Multivariable linear regression models were used to examine associations of cord and maternal metabolites with infant anthropometry at birth. RESULTS: In cord blood samples from this rural cohort from New Hampshire of largely white residents, 13 metabolites showed negative associations, and 10 metabolites showed positive associations with birth weight Z-score. Acylcarnitine C5 showed negative association, and 4 lysophosphatidylcholines showed positive associations with birth length Z-score. Maternal blood metabolites did not significantly correlate with birth weight and length Z-scores. CONCLUSIONS: Consistent findings were observed for several acylcarnitines that play a role in utilization of energy sources, and a lysophosphatidylcholine that is part of oxidative stress and inflammatory response pathways in cord plasma samples. IMPACT: The metabolomics profiles of maternal plasma during pregnancy and cord plasma at birth may influence fetal growth and birth anthropometry. This study examines the independent effects of maternal gestational and infant cord blood metabolomes across different classes of metabolites on birth anthropometry. Acylcarnitine species were negatively associated and glycerophospholipids species were positively associated with weight and length Z-scores at birth in the cord plasma samples, but not in the maternal plasma samples. This study identifies lipid metabolites in infants that possibly may affect early growth.

Inter-method reliability of silicone exposome wristbands and urinary biomarker assays in a pregnancy cohort.

Silicone wristbands act as passive environmental samplers capable of detecting and measuring concentrations of a variety of chemicals. They offer a noninvasive method to collect complex exposure data in large-scale epidemiological studies. We evaluated the inter-method reliability of silicone wristbands and urinary biomarkers in the New Hampshire Birth Cohort Study. A subset of study participants (n = 96) provided a urine sample and wore a silicone wristband for 7 days at approximately 12 gestational weeks. Women were instructed to wear the wristbands during all their normal activities. Concentrations of urinary compounds and metabolites in the urine and parent compounds in wristbands were compared. High detection rates were observed for triphenyl phosphate (76.0%) and benzophenone (78.1%) in wristbands, although the distribution of corresponding urinary concentrations of chemicals did not differ according to whether chemicals were detected or not detected in wristbands. While detected among only 8.3% of wristbands, median urinary triclosan concentrations were higher among those with triclosan detected in wristbands (9.04 ng/mL) than without (0.16 ng/mL). For most chemicals slight to fair agreement was observed across exposure assessment methods, potentially due to low rates of detection in the wristbands for chemicals where observed urinary concentrations were relatively low as compared to background concentrations in the general population. Our findings support the growing body of research in support of deploying silicone wristbands as an important exposure assessment tool.

Association between peri-conceptional bisphenol A exposure in women and men and time to pregnancy-The HOPE study.

BACKGROUND: Bisphenol A (BPA) is a non-persistent endocrine-disrupting chemical with nearly ubiquitous, involuntary exposure. Previous studies have shown that BPA causes reproductive dysfunction in animal models, but there are limited data regarding the effects of BPA exposure on time to pregnancy (TTP) in humans. OBJECTIVE: To evaluate whether peri-conceptional BPA exposure of women and men is associated with couples' TTP. METHODS: A total of 164 heterosexual couples (164 women; 163 men) who have available BPA information as well as time to pregnancy from the Home Observation of Peri-conceptional Exposures (HOPE) Study were included and were followed up to 12 months. Women collected first-morning urine samples starting at the beginning of the fertile window and continued until the onset of menses or 18 days after the estimated day of ovulation (EDO+18 days). The time to pregnancy (TTP) after the enrolment was self-reported and used for the analysis. Discrete-time Cox proportional hazards models were performed to generate fecundability odds ratio (FOR) between BPA and TTP after adjusting for education and age, accounting for right censoring and prior number of cycles trying to conceive. RESULTS: Among 164 couples, 125 couples became pregnant during the study. There was no association between TTP and peri-conceptional BPA exposure for both men (FOR 1.02, 95% CI 0.72, 1.47) and women (FOR 1.07, 95% CI 0.75, 1.53) after adjusting for education and age. CONCLUSIONS: No association was found between peri-conceptional BPA exposure and fecundability in this preconception cohort of relatively young, healthy pregnancy planners.

Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles.

The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, as it does at concentrations routinely used in cell culture. However, we determine here that paclitaxel levels in primary breast tumors are well below those required to elicit sustained mitotic arrest. Instead, cells in these lower concentrations of drug proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting in chromosome missegregation and cell death. Consistent with these cell culture data, most mitotic cells in primary human breast cancers contain multipolar spindles after paclitaxel treatment. Contrary to the previous hypothesis, we find that mitotic arrest is dispensable for tumor regression in patients. These results demonstrate that mitotic arrest is not responsible for the efficacy of paclitaxel, which occurs because of chromosome missegregation on highly abnormal, multipolar spindles. This mechanistic insight may be used to improve selection of future antimitotic drugs and to identify a biomarker with which to select patients likely to benefit from paclitaxel.