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.

Evidence of a Role for the Hippocampus in Food-Cue Processing and the Association with Body Weight and Dietary Added Sugar.

OBJECTIVE: The current analysis used functional magnetic resonance imaging (fMRI) to explore a model of energy regulation postulating that the hippocampus integrates interoceptive signals and environmental stimuli to suppress responding to food cues. It was hypothesized that hippocampal activity would increase in response to food cues under postnutritive relative to fasted conditions, given the role of the hippocampus in integrating postnutritive signals with food cues, and that obesity, added sugar intake, or a combination of these factors would alter this response. METHODS: Data were analyzed on 65 participants (29 males). Participants consumed drinks containing 75 g of glucose or water and underwent an fMRI-based food-cue task. Blood-oxygen-level-dependent (BOLD) fMRI was used to examine hippocampal responses to food and nonfood cues. RESULTS: In lean participants, the hippocampal BOLD signal was higher following glucose compared with water, but participants with obesity showed the opposite pattern. BMI interacted with added sugar intake such that BMI was more negatively correlated with hippocampal food-cue reactivity after glucose ingestion in individuals who consumed high levels of added sugar. Hippocampal BOLD was negatively correlated with prospective food intake. CONCLUSIONS: The findings are consistent with the view that energy regulation involves hippocampal processes in humans and that added sugar and excess weight may impair this function.

Appetite-Regulating Hormones Are Reduced After Oral Sucrose vs Glucose: Influence of Obesity, Insulin Resistance, and Sex.

CONTEXT: Fructose compared to glucose has adverse effects on metabolic function, but endocrine responses to oral sucrose vs glucose is not well understood. OBJECTIVE: We investigated how oral sucrose vs glucose affected appetite-regulating hormones, and how biological factors (body mass index [BMI], insulin sensitivity, sex) influence endocrine responses to these 2 types of sugar. DESIGN: Sixty-nine adults (29 men; 23.22 ±â€…3.74 years; BMI 27.03 ±â€…4.96 kg/m2) completed the study. On 2 occasions, participants consumed 300-mL drinks containing 75 g of glucose or sucrose. Blood was sampled at baseline, 10, 35, and 120 minutes post drink for plasma glucose, insulin, glucagon-like peptide (GLP-1)(7-36), peptide YY (PYY)total, and acyl-ghrelin measures. Hormone levels were compared between conditions using a linear mixed model. Interaction models were performed, and results were stratified to assess how biological factors influence endocrine responses. RESULTS: Sucrose vs glucose ingestion provoked a less robust rise in glucose (P < .001), insulin (P < .001), GLP-1 (P < .001), and PYY (P = .02), whereas acyl-ghrelin suppression was similar between the sugars. We found BMI status by sugar interactions for glucose (P = .01) and PYY (P = .03); obese individuals had smaller increases in glucose and PYY levels after consuming sucrose vs glucose. There were interactions between insulin sensitivity and sugar for glucose (P = .003) and insulin (P = .04), and a sex by sugar interaction for GLP-1 (P = .01); men demonstrated smaller increases in GLP-1 in response to oral sucrose vs glucose. CONCLUSION: Sucrose is less efficient at signaling postprandial satiation than glucose, and biological factors influence differential hormone responses to sucrose vs glucose consumption.

Distinct Circuits for Recovery of Eye Dominance and Acuity in Murine Amblyopia.

Degrading vision by one eye during a developmental critical period yields enduring deficits in both eye dominance and visual acuity. A predominant model is that "reactivating" ocular dominance (OD) plasticity after the critical period is required to improve acuity in amblyopic adults. However, here we demonstrate that plasticity of eye dominance and acuity are independent and restricted by the nogo-66 receptor (ngr1) in distinct neuronal populations. Ngr1 mutant mice display greater excitatory synaptic input onto both inhibitory and excitatory neurons with restoration of normal vision. Deleting ngr1 in excitatory cortical neurons permits recovery of eye dominance but not acuity. Reciprocally, deleting ngr1 in thalamus is insufficient to rectify eye dominance but yields improvement of acuity to normal. Abolishing ngr1 expression in adult mice also promotes recovery of acuity. Together, these findings challenge the notion that mechanisms for OD plasticity contribute to the alterations in circuitry that restore acuity in amblyopia.

Influences of Dietary Added Sugar Consumption on Striatal Food-Cue Reactivity and Postprandial GLP-1 Response.

Sugar consumption in the United States exceeds recommendations from the American Heart Association. Overconsumption of sugar is linked to risk for obesity and metabolic disease. Animal studies suggest that high-sugar diets alter functions in brain regions associated with reward processing, including the dorsal and ventral striatum. Human neuroimaging studies have shown that these regions are responsive to food cues, and that the gut-derived satiety hormones, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY), suppress striatal food-cue responsivity. We aimed to determine the associations between dietary added sugar intake, striatal responsivity to food cues, and postprandial GLP-1 and PYY levels. Twenty-two lean volunteers underwent a functional magnetic resonance imaging (fMRI) scan during which they viewed pictures of food and non-food items after a 12-h fast. Before scanning, participants consumed a glucose drink. A subset of 19 participants underwent an additional fMRI session in which they consumed water as a control condition. Blood was sampled for GLP-1, and PYY levels and hunger ratings were assessed before and ~75 min after drink consumption. In-person 24-h dietary recalls were collected from each participant on three to six separate occasions over a 2-month period. Average percent calories from added sugar were calculated using information from 24-h dietary recalls. A region-of-interest analysis was performed to compare the blood oxygen level-dependent (BOLD) response to food vs. non-food cues in the bilateral dorsal striatum (caudate/putamen) and ventral striatum (nucleus accumbens). The relationships between added sugar, striatal responses, and hormone changes after drink consumption were assessed using Spearman's correlations. We observed a positive correlation between added sugar intake and BOLD response to food cues in the dorsal striatum and a similar trend in the nucleus accumbens after glucose, but not water, consumption. Added sugar intake was negatively associated with GLP-1 response to glucose. Post hoc analysis revealed a negative correlation between GLP-1 response to glucose and BOLD response to food cues in the dorsal striatum. Our findings suggest that habitual added sugar intake is related to increased striatal response to food cues and decreased GLP-1 release following glucose intake, which could contribute to susceptibility to overeating.

Nogo Receptor 1 Limits Ocular Dominance Plasticity but not Turnover of Axonal Boutons in a Model of Amblyopia.

The formation and stability of dendritic spines on excitatory cortical neurons are correlated with adult visual plasticity, yet how the formation, loss, and stability of postsynaptic spines register with that of presynaptic axonal varicosities is unknown. Monocular deprivation has been demonstrated to increase the rate of formation of dendritic spines in visual cortex. However, we find that monocular deprivation does not alter the dynamics of intracortical axonal boutons in visual cortex of either adult wild-type (WT) mice or adult NgR1 mutant (ngr1-/-) mice that retain critical period visual plasticity. Restoring normal vision for a week following long-term monocular deprivation (LTMD), a model of amblyopia, partially restores ocular dominance (OD) in WT and ngr1-/- mice but does not alter the formation or stability of axonal boutons. Both WT and ngr1-/- mice displayed a rapid return of normal OD within 8 days after LTMD as measured with optical imaging of intrinsic signals. In contrast, single-unit recordings revealed that ngr1-/- exhibited greater recovery of OD by 8 days post-LTMD. Our findings support a model of structural plasticity in which changes in synaptic connectivity are largely postsynaptic. In contrast, axonal boutons appear to be stable during changes in cortical circuit function.

Nogo receptor 1 limits tactile task performance independent of basal anatomical plasticity.

The genes that govern how experience refines neural circuitry and alters synaptic structural plasticity are poorly understood. The nogo-66 receptor 1 gene (ngr1) is one candidate that may restrict the rate of learning as well as basal anatomical plasticity in adult cerebral cortex. To investigate if ngr1 limits the rate of learning we tested adult ngr1 null mice on a tactile learning task. Ngr1 mutants display greater overall performance despite a normal rate of improvement on the gap-cross assay, a whisker-dependent learning paradigm. To determine if ngr1 restricts basal anatomical plasticity in the associated sensory cortex, we repeatedly imaged dendritic spines and axonal varicosities of both constitutive and conditional adult ngr1 mutant mice in somatosensory barrel cortex for two weeks through cranial windows with two-photon chronic in vivo imaging. Neither constant nor acute deletion of ngr1 affected turnover or stability of dendritic spines or axonal boutons. The improved performance on the gap-cross task is not attributable to greater motor coordination, as ngr1 mutant mice possess a mild deficit in overall performance and a normal learning rate on the rotarod, a motor task. Mice lacking ngr1 also exhibit normal induction of tone-associated fear conditioning yet accelerated fear extinction and impaired consolidation. Thus, ngr1 alters tactile and motor task performance but does not appear to limit the rate of tactile or motor learning, nor determine the low set point for synaptic turnover in sensory cortex.

Plasticity of binocularity and visual acuity are differentially limited by nogo receptor.

The closure of developmental critical periods consolidates neural circuitry but also limits recovery from early abnormal sensory experience. Degrading vision by one eye throughout a critical period both perturbs ocular dominance (OD) in primary visual cortex and impairs visual acuity permanently. Yet understanding how binocularity and visual acuity interrelate has proven elusive. Here we demonstrate the plasticity of binocularity and acuity are separable and differentially regulated by the neuronal nogo receptor 1 (NgR1). Mice lacking NgR1 display developmental OD plasticity as adults and their visual acuity spontaneously improves after prolonged monocular deprivation. Restricting deletion of NgR1 to either cortical interneurons or a subclass of parvalbumin (PV)-positive interneurons alters intralaminar synaptic connectivity in visual cortex and prevents closure of the critical period for OD plasticity. However, loss of NgR1 in PV neurons does not rescue deficits in acuity induced by chronic visual deprivation. Thus, NgR1 functions with PV interneurons to limit plasticity of binocularity, but its expression is required more extensively within brain circuitry to limit improvement of visual acuity following chronic deprivation.