Chronic failure to suppress intake during states of positive energy balance leads to weight gain and obesity. The ability to use context – including interoceptive satiety states – to inhibit responding to previously rewarded cues appears to depend on the functional integrity of the hippocampus. Recent evidence implicates energy dense Western diets in several types of hippocampal dysfunction, including reduced expression of neurotrophins and nutrient transporters, increased inflammation, microglial activation, and blood brain barrier permeability. The functional consequences of such insults include impairments in an animal’s ability to modulate responding to a previously reinforced cues. We propose that such deficits promote overeating, which can further exacerbate hippocampal dysfunction and thus initiate a vicious cycle of both obesity and progressive cognitive decline.

Over the past decade, a great deal of research has established the importance of cognitive processes in the control of energy intake and body weight. The present paper begins by identifying several of these cognitive processes. We then summarize evidence from human and nonhuman animal models, which shows how excess intake of obesity-promoting Western diet (WD) may have deleterious effects on these cognitive control processes. Findings that these effects may be manifested as early-life deficits in cognitive functioning and may also be associated with the emergence of serious late-life cognitive impairment are described. Consistent with these possibilities, we review evidence, obtained primarily from rodent models, that consuming a WD is associated with the emergence of pathophysiologies in the hippocampus, an important brain substrate for learning, memory, and cognition. The implications of this research for mechanism are discussed within the context of a “vicious-cycle model,” which describes how eating a WD could impair hippocampal function, producing cognitive deficits that promote increased WD intake and body weight gain, which could contribute to further hippocampal dysfunction, cognitive decline, and excess eating and weight gain.

In western and westernized societies, large portions of the population live in what are considered to be “obesogenic” environments. Among other things, obesogenic environments are characterized by a high prevalence of external cues that are associated with highly palatable, energy-dense foods. One prominent hypothesis suggests that these external cues become such powerful conditioned elicitors of appetitive and eating behavior that they overwhelm the internal, physiological mechanisms that serve to maintain energy balance. The present research investigated a learning mechanism that may underlie this loss of internal relative to external control. In Experiment 1, rats were provided with both auditory cues (external stimuli) and varying levels of food deprivation (internal stimuli) that they could use to solve a simple discrimination task. Despite having access to clearly discriminable external cues, we found that the deprivation cues gained substantial discriminative control over conditioned responding. Experiment 2 found that, compared to standard chow, maintenance on a “western-style” diet high in saturated fat and sugar weakened discriminative control by food deprivation cues, but did not impair learning when external cues were also trained as relevant discriminative signals for sucrose. Thus, eating a western-style diet contributed to a loss of internal control over appetitive behavior relative to external cues. We discuss how this relative loss of control by food deprivation signals may result from interference with hippocampal-dependent learning and memory processes, forming the basis of a vicious-cycle of excessive intake, body weight gain, and progressive cognitive decline that may begin very early in life.

In obesogenic environments food-related external cues are thought to overwhelm internal cues that normally regulate energy intake. We investigated how this shift from external to internal stimulus control might occur. Experiment 1 showed that rats could use stimuli arising from 0 and 4h food deprivation to predict sucrose delivery. Experiment 2 then examined (a) the ability of these deprivation cues to compete with external cues and (b) how consuming a Western-style diet (WD) affects that competition. Rats were trained to use both their deprivation cues and external cues as compound discriminative stimuli. Half of the rats were then placed on WD while the others remained on chow, and external cues were removed to assess learning about deprivation state cues. When tested with external cues removed, chow-fed rats continued to discriminate using only deprivation cues, while WD-fed rats did not. The WD-fed group performed similarly to control groups trained with a noncontingent relationship between deprivation cues and sucrose reinforcement. Previous studies provided evidence that discrimination based on interoceptive deprivation cues depends on the hippocampus and that WD intake could interfere with hippocampal functioning. A third experiment assessed the effects of neurotoxic hippocampal lesions on weight gain and on sensitivity to the appetite-suppressing effects of the satiety hormone cholecystokinin (CCK). Relative to controls, hippocampal-lesioned rats gained more weight and showed reduced sensitivity to a 1.0 ug but not 2.0 or 4.0 ug CCK doses. These findings suggest that WD intake reduces utilization of interoceptive energy state signals to regulate appetitive behavior via a mechanism that involves the hippocampus.

Males and females show distinct differences in action potential waveform, ion channel expression patterns, and ECG characteristics. However, it is not known how sex-based differences in Ca 2ϩ cycling might contribute to these differences in electrophysiological activity. The goal of this study was to investigate the differences in cellular Ca 2ϩ transients in males and females and to examine how these might contribute to electrophysiological function. Ca 2ϩ transients were measured in individual myocytes within microscopic regions of the fluo-4 AM-loaded left ventricular epicardium of intact rat heart of both sexes (3 to 5 mo old). Pacing protocols were used to measure transient characteristics at a basic cycle length of 500 ms and during 10-s trains of rapid pacing delivered to the left ventricular apex. Ca 2ϩ transients were smaller in magnitude and longer in duration in females than in males. More importantly, the variability in Ca 2ϩ transient characteristics between myocytes in a microscopic recording site (heterogeneity index) was greater for females than males for characteristics related to transient duration. The rate sensitivity of Ca 2ϩ alternans development in individual myocytes was greater in females than in males, but there was also a greater heterogeneity in cellular responses to the rate dependence of alternans development in females. The longer Ca 2ϩ transients in females were also associated with slower restitution, which was likely to be responsible for the development of Ca 2ϩ and repolarization alternans at slower heart rates. These results demonstrate that there are distinct differences in cellular Ca 2ϩ cycling in male and female rat hearts. Not only is there slower reuptake of Ca 2ϩ in female rats, but there is greater local variability in Ca 2ϩ cycling at the microscopic level. These sex-based differences in Ca 2ϩ cycling could contribute to differences in ECG morphology and in arrhythmia sensitivity in males and females. calcium transients; intercellular heterogeneity; confocal microscopy; T-wave alternans; calcium alternans; restitution IT IS KNOWN THAT women are more sensitive to both genetic and acquired long QT syndrome-based arrhythmias and bradycardia-induced torsades de pointes, whereas men are more likely to develop atrial fibrillation, early repolarization, and Brugada syndromes and sudden cardiac death (9). It has been suggested that one of the reasons underlying this difference is the combination of higher heart rate and longer QT interval in women (9), although the mechanisms by which these differences in the characteristics of the electrocardiogram (ECG) could influence cardiac electrophysiological behavior at the cell and organ level have not been described. There are now many reports of sex differences in ion channel expression patterns in a number of species including dog (23), rabbit (13, 15), guinea pig (8), rat (12), and humans (9, 15) that could account for some of the electrophysiological differences in males and females, particularly in action potential (AP) durati...

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 foodcue 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.

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 ± 3.74 years; BMI 27.03 ± 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.

In rodent literature, there is evidence that excessive fructose consumption during development has a detrimental impact on hippocampal structure and function. In this study of 103 children ages 7–11 years old, we investigated whether dietary fructose intake was related to alterations in hippocampal volume and connectivity in humans. To examine if these associations were specific to fructose or were related to dietary sugars intake in general, we explored relationships between dietary intake of added sugars and the monosaccharide, glucose, on the same brain measures. We found that increased dietary intake of fructose, measured as a percentage of total calories, was associated with both an increase in the volume of the CA2/3 subfield of the right hippocampus and increased axial, radial, and mean diffusivity in the prefrontal connections of the right cingulum. These findings are consistent with the idea that increased fructose consumption during childhood may be associated with an inflammatory process, and/or decreases or delays in myelination and/or pruning. Increased habitual consumption of glucose or added sugar in general were associated with an increased volume of right CA2/3, but not with any changes in the connectivity of the hippocampus. These findings support animal data suggesting that higher dietary intake of added sugars, particularly fructose, are associated with alterations in hippocampal structure and connectivity during childhood.