Abstract
Context
Behavioral studies suggest that responses to food consumption are altered in children with obesity (OB).
Objective
To test central nervous system and peripheral hormone response by ...functional MRI and satiety-regulating hormone levels before and after a meal.
Design and Setting
Cross-sectional study comparing children with OB and children of healthy weight (HW) recruited from across the Puget Sound region of Washington.
Participants
Children (9 to 11 years old; OB, n = 54; HW, n = 22), matched for age and sex.
Intervention and Outcome Measures
Neural activation to images of high- and low-calorie food and objects was evaluated across a set of a priori appetite-processing regions that included the ventral and dorsal striatum, amygdala, substantia nigra/ventral tegmental area, insula, and medial orbitofrontal cortex. Premeal and postmeal hormones (insulin, peptide YY, glucagon-like peptide-1, active ghrelin) were measured.
Results
In response to a meal, average brain activation by high-calorie food cues vs objects in a priori regions was reduced after meals in children of HW (Z = −3.5, P < 0.0001), but not in children with OB (z = 0.28, P = 0.78) despite appropriate meal responses by gut hormones. Although premeal average brain activation by high-calorie food cues was lower in children with OB vs children of HW, postmeal activation was higher in children with OB (Z = −2.1, P = 0.04 and Z = 2.3, P = 0.02, respectively). An attenuated central response to a meal was associated with greater degree of insulin resistance.
Conclusions
Our data suggest that children with OB exhibit an attenuated central, as opposed to gut hormone, response to a meal, which may predispose them to overconsumption of food or difficulty with weight loss.
Using functional neuroimaging to test visual food cue responses before and after a meal, we found an attenuated central satiety and normal gut hormone response in 9- to 11-year-old children with obesity.
Objective
To use quantitative magnetic resonance imaging (MRI) to test whether mediobasal hypothalamic (MBH) gliosis is associated with obesity and insulin resistance in humans.
Methods
Sixty‐seven ...participants underwent a fasting blood draw and MRI. Cases with radiologic evidence of MBH gliosis (N = 22) were identified as the upper tertile of left MBH T2 relaxation time and were compared to controls (N = 23) from the lowest tertile. In a separate postmortem study, brain slices (N = 10) through the MBH were imaged by MRI and stained for glial fibrillary acidic protein (GFAP).
Results
In all participants, longer T2 relaxation time in the left MBH was associated with higher BMI (P = 0.01). Compared with controls, cases had longer T2 relaxation times in the right MBH (P < 0.05), as well as higher BMI (P < 0.05), fasting insulin concentrations (P < 0.01), and HOMA‐IR values (P < 0.01), adjusted for sex and age. Elevations in insulin and HOMA‐IR were also independent of BMI. In the postmortem study, GFAP staining intensity was positively associated with MBH T2 relaxation time (P < 0.05), validating an MRI‐based method for the detection of MBH gliosis in humans.
Conclusions
These findings link hypothalamic gliosis to insulin resistance in humans and suggest that the link is independent of the level of adiposity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Obesity interventions often result in increased motivation to eat.
We investigated relationships between obesity outcomes and changes in brain activation by visual food cues and hormone levels in ...response to obesity intervention by family-based behavioral treatment (FBT).
Neuroimaging and hormone assessments were conducted before and after 24-week FBT intervention in children with obesity (OB, n = 28), or children of healthy weight without intervention (HW, n = 17), all 9- to 11-year-old boys and girls. We evaluated meal-induced changes in neural activation to high- vs low-calorie food cues across appetite-processing brain regions and gut hormones.
Among children with OB who underwent FBT, greater declines of BMI z-score were associated with lesser reductions after the FBT intervention in meal-induced changes in neural activation to high- vs low-calorie food cues across appetite-processing brain regions (P < 0.05), and the slope of relationship was significantly different compared with children of HW. In children with OB, less reduction in brain responses to a meal from before to after FBT was associated with greater meal-induced reduction in ghrelin and increased meal-induced stimulation in peptide YY and glucagon-like peptide-1 (all P < 0.05).
In response to FBT, adaptations of central satiety responses and peripheral satiety-regulating hormones were noted. After weight loss, changes of peripheral hormone secretion support weight loss, but there was a weaker central satiety response. The findings suggest that even when peripheral satiety responses by gut hormones are intact, the central regulation of satiety is disturbed in children with OB who significantly improve their weight status during FBT, which could favor future weight regain.
Objective
This study aimed to determine whether a relationship was evident between gliosis in the mediobasal hypothalamus (MBH) and plasma testosterone concentrations in men.
Methods
A total of 41 ...adult men (aged 18‐50 years) from 23 twin pairs underwent fasting morning blood draw and brain magnetic resonance imaging. T2 relaxation time was used to quantify gliosis in the MBH and control areas in the putamen and amygdala. Plasma concentrations of testosterone and 17β‐estradiol were measured by liquid chromatography‐tandem mass spectrometry. Body composition including visceral adiposity was measured by dual x‐ray absorptiometry.
Results
A negative association was found between MBH T2 relaxation time and plasma concentrations of both free and total testosterone (r = −0.29, P < 0.05 and r = −0.37, P < 0.01, respectively). Visceral adiposity exhibited a negative correlation with plasma total testosterone concentration (r = −0.45, P = 0.001) but a positive correlation with MBH T2 relaxation time (r = 0.24, P = 0.03). The negative correlation between plasma total testosterone and MBH T2 relaxation time remained significant after adjustment for visceral adiposity, age, BMI, and insulin resistance.
Conclusions
In healthy men across a range of BMIs, MBH gliosis was associated with higher visceral adiposity but lower endogenous testosterone. These findings suggest that MBH gliosis could provide novel mechanistic insights into gonadal dysfunction in men with obesity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The salience network (SN) comprises brain regions that evaluate cues in the external environment in light of internal signals. We examined the SN response to meal intake and potential genetic and ...acquired influences on SN function.
Monozygotic (MZ; 40 pairs) and dizygotic (15 pairs) twins had body composition and plasma metabolic profile evaluated (glucose, insulin, leptin, ghrelin, and GLP-1). Twins underwent resting-state functional magnetic resonance imaging (fMRI) scans before and after a standardized meal. The strength of SN connectivity was analyzed pre- and post-meal and the percentage change elicited by a meal was calculated. A multi-echo T2 MRI scan measured T2 relaxation time, a radiologic index of gliosis, in the mediobasal hypothalamus (MBH) and control regions. Statistical approaches included intraclass correlations (ICC) to investigate genetic influences and within-pair analyses to exclude genetic confounders.
SN connectivity was reduced by a meal ingestion (β = -0.20; P < 0.001). Inherited influences on both pre- and post-meal connectivity were present (ICC MZ twins 26%, P < 0.05 and 47%, P < 0.001, respectively), but not percentage change in response to the meal. SN connectivity in response to a meal did not differ between participants with obesity and of normal weight (χ2(1) = 0.93; P = 0.33). However, when participants were classified as having high or low signs of MBH gliosis, the high MBH gliosis group failed to reduce the connectivity in response to a meal (z = -1.32; P = 0.19). Excluding genetic confounders, the percentage change in SN connectivity by a meal correlated to body fat percentage (r = 0.24; P < 0.01).
SN connectivity was reduced by a meal, indicating potential participation of the SN in control of feeding. The strength of SN connectivity is inherited, but the degree to which SN connectivity is reduced by eating appears to be influenced by adiposity and the presence of hypothalamic gliosis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Family-based behavioral treatment (FBT) is the recommended treatment for children with common obesity. However, there is a large variability in short- and long-term treatment response, and mechanisms ...for unsuccessful treatment outcomes are not fully understood. In this study, we tested if brain response to visual food cues among children with obesity before treatment predicted weight or behavioral outcomes during a 6-month behavioral weight management program and/or long-term relative weight maintenance over a 1-year follow-up period.
Thirty-seven children with obesity (age 9-11 years, 62% male) who entered active FBT (attended two or more sessions) and had outcome data. Brain activation was assessed at pretreatment by functional magnetic resonance imaging across an a priori set of appetite-processing brain regions that included the ventral and dorsal striatum, mOFC, amygdala, substantia nigra/ventral tegmental area, and insula in response to viewing food images before and after a standardized meal.
Children with more robust reductions in brain activation to high-calorie food cue images following a meal had greater declines in BMI z-score during FBT (r = 0.42; 95% CI: 0.09, 0.66; P = 0.02) and greater improvements in Healthy Eating Index scores (r = -0.41; 95% CI: -0.67, -0.06; P = 0.02). In whole-brain analyses, greater activation in the ventromedial prefrontal cortex, specifically by high-calorie food cues, was predictive of better treatment outcomes (whole-brain cluster corrected P = 0.02). There were no significant predictors of relative weight maintenance, and initial behavioral or hormonal measures did not predict FBT outcomes.
Children's brain responses to a meal prior to obesity treatment were related to treatment-based weight outcomes, suggesting that neurophysiologic factors and appetitive drive, more so than initial hormone status or behavioral characteristics, limit intervention success.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
FTO genotype impacts food intake and corticolimbic activation Melhorn, Susan J; Askren, Mary K; Chung, Wendy K ...
The American journal of clinical nutrition,
February 2018, 2018-02-01, 2018-02-00, 20180201, Volume:
107, Issue:
2
Journal Article
Peer reviewed
Open access
Variants in the first intron of the fat mass and obesity-associated (FTO) gene increase obesity risk. People with “high-risk” FTO genotypes exhibit preference for high-fat foods, reduced satiety ...responsiveness, and greater food intake consistent with impaired satiety.
We sought central nervous system mechanisms that might underlie impaired satiety perception in people with a higher risk of obesity based on their FTO genotype.
We performed a cross-sectional study in a sample that was enriched for obesity and included 20 higher-risk participants with the AA (risk) genotype at the rs9939609 locus of FTO and 94 lower-risk participants with either the AT or TT genotype. We compared subjective appetite, appetite-regulating hormones, caloric intake at a buffet meal, and brain response to visual food cues in an extended satiety network using functional MRI scans acquired before and after a standardized meal.
Higher-risk participants reported less subjective fullness (χ2 = 7.48, P < 0.01), rated calorie-dense food as more appealing (χ2 = 3.92, P < 0.05), and consumed 350 more kilocalories than lower-risk participants (β = 348 kcal, P = 0.03), even after adjusting for fat or lean mass. Premeal, the higher-risk group had greater activation by “fattening” food images (compared with objects) in the medial orbital frontal cortex (β = 11.6; 95% CI: 1.5, 21.7; P < 0.05). Postmeal, the higher-risk subjects had greater activation by fattening (compared with nonfattening) food cues in the ventral tegmental area/substantia nigra (β = 12.8; 95% CI: 2.7, 23.0; P < 0.05), amygdala (β = 10.6; 95% CI: 0.7, 20.5; P < 0.05), and ventral striatum (β = 6.9; 95% CI: 0.2, 13.7; P < 0.05). Moreover, postmeal activation by fattening food cues within the preselected extended satiety network was positively associated with energy intake at the buffet meal (R2 = 0.29, P = 0.04) and this relation was particularly strong in the dorsal striatum (R2 = 0.28, P = 0.01), amygdala (R2 = 0.28, P = 0.03), and ventral tegmental area/substantia nigra (R2 = 0.27, P = 0.01).
The findings are consistent with a model in which allelic variants in FTO raise obesity risk through impaired central nervous system satiety processing, thereby increasing food intake. This study is registered at clinicaltrials.gov as NCT02483663.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Preclinical research implicates hypothalamic glial cell responses in the pathogenesis of obesity and type 2 diabetes (T2D). In the current study we sought to translate such findings to humans by ...testing whether radiologic markers of gliosis in the mediobasal hypothalamus (MBH) were greater in individuals with obesity and impaired glucose homeostasis or T2D.
Using cross-sectional and prospective cohort study designs, we applied a validated quantitative MRI approach to assess gliosis in 67 adults with obesity and normal glucose tolerance, impaired glucose tolerance (IGT), or T2D. Assessments of glucose homeostasis were conducted via oral glucose tolerance tests (OGTT) and β-cell modeling.
We found significantly greater T2 relaxation times (a marker of gliosis by MRI), that were independent of adiposity, in the groups with IGT and T2D as compared with the group with normal glucose tolerance. Findings were present in the MBH, but not control regions. Moreover, positive linear associations were present in the MBH but not control regions between T2 relaxation time and glucose area under the curve during an OGTT, fasting glucose concentrations, hemoglobin A1c, and visceral adipose tissue mass, whereas negative linear relationships were present in the MBH for markers of insulin sensitivity and β-cell function. In a prospective cohort study, greater MBH T2 relaxation times predicted declining insulin sensitivity over 1 year.
Findings support a role for hypothalamic gliosis in the progression of insulin resistance in obesity and thus T2D pathogenesis in humans.
Studies demonstrate evidence of gliosis in the mediobasal hypothalamus (MBH) of people with obesity and T2D or impaired glucose tolerance (IGT), but whether MBH gliosis predicts worsening glucose ...homeostasis is unknown.
The study evaluated 38 subjects with obesity (68% female, 76% White). Mean age was 47±11 y and BMI was 35±3.9 kg/m2. MRI, DXA, and 75 g OGTT were performed at baseline and DXA and OGTT repeated at 1y. Mean bilateral T2 relaxation time (ms) in the MBH and 3 control regions was measured as a marker of gliosis. Serial blood samples from OGTT were used to calculate glucose area under the curve (incremental iAUC and total totalAUC) and to model insulin sensitivity (OGIS) and beta-cell function (beta-cell glucose sensitivity). Generalized estimating equations tested associations and interactions by region.
On average, measures of glucose tolerance (iAUC and totalAUC), OGIS, and beta-cell glucose sensitivity were stable over 1 y. Baseline bilateral mean MBH T2 relaxation time was not associated with changes in glucose tolerance (Δ iAUC β: -5.8 ms, 95% CI -21.0, 9.4, P=0.45; Δ totalAUC β: 1.3 ms, 95% CI -33.5, 36.0, P=0.94, adjusted for sex, age) or change in glucose sensitivity (β: 0.3 ms, 95% CI -1.0, 1.6, P=0.66) nor were interactions present. Change in OGIS over 1y was significantly negatively associated with bilateral mean MBH T2 relaxation time at baseline (β: -0.94 ms, 95% CI -1.7, -0.2, P=0.02, adjusted for sex, age); subjects with longer MBH T2 relaxation times at baseline reduced OGIS over 1 y. A formal interaction by region was not significant (chi2(7)=7.11, Pint=0.42). The relationship within the MBH was attenuated when also adjusted for change in fat mass (β: -0.70 ms 95% CI -1.4, 0.02, P=0.056).
Subjects with greater radiologic evidence for MBH gliosis exhibited declines in insulin sensitivity over 1 y which were not fully accounted for by changes in adiposity. These longitudinal findings are consistent with a role for MBH gliosis in T2D pathogenesis in people with obesity.
Disclosure
J. L. Rosenbaum: None. S. Schoen: None. S. J. Melhorn: None. M. De leon: None. M. Webb: None. K. Utzschneider: None. E. Schur: None.
Funding
American Diabetes Association (1-17-ICTS-085 to E.S.)
•Neuroimaging studies suggest that appetitive drive is enhanced in obesity.•Brain response to food cues in appetite-regulating regions was assessed in adult twins.•Controlled for genetics, fat mass ...was unrelated to regional brain response to food cues.•Lower fat mass correlated with greater activation in the dorsolateral prefrontal cortex.•In adult twins, the level of adiposity was not associated with excess appetitive drive.
Neuroimaging studies suggest that appetitive drive is enhanced in obesity.
To test if appetitive drive varies in direct proportion to the level of body adiposity after accounting for genetic factors that contribute to both brain response and obesity risk.
Participants were adult monozygotic (n = 54) and dizygotic (n = 30) twins with at least one member of the pair with obesity. Body composition was assessed by dual-energy X-ray absorptiometry. Hormonal and appetite measures were obtained in response to a standardized meal that provided 20% of estimated daily caloric needs and to an ad libitum buffet meal. Pre- and post-meal functional magnetic resonance imaging (fMRI) assessed brain response to visual food cues in a set of a priori appetite-regulating regions. Exploratory voxelwise analyses outside a priori regions were performed with correction for multiple comparisons.
In a group of 84 adults, the majority with obesity (75%), body fat mass was not associated with hormonal responses to a meal (glucose, insulin, glucagon-like peptide-1 and ghrelin, all P>0.40), subjective feelings of hunger (β=−0.01 mm 95% CI −0.35, 0.34 P = 0.97) and fullness (β=0.15 mm −0.15, 0.44 P = 0.33), or buffet meal intake in relation to estimated daily caloric needs (β=0.28% −0.05, 0.60 P = 0.10). Body fat mass was also not associated with brain response to high-calorie food cues in appetite-regulating regions (Pre-meal β=−0.12 −0.32, 0.09 P = 0.26; Post-meal β=0.18 −0.02, 0.37 P = 0.09; Change by a meal β=0.29 −0.02, 0.61 P = 0.07). Conversely, lower fat mass was associated with being weight reduced (β=−0.05% −0.07, −0.03 P<0.001) and greater pre-meal activation to high-calorie food cues in the dorsolateral prefrontal cortex (Z = 3.63 P = 0.017).
In a large study of adult twins, the majority with overweight or obesity, the level of adiposity was not associated with excess appetitive drive as assessed by behavioral, hormonal, or fMRI measures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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