Intake of a Western diet (WD), which is high in saturated fat and sugar, is associated with deficits in hippocampal-dependent learning and memory processes as well as with markers of hippocampal pathology. In the present study, rats were trained to asymptote on hippocampal-dependent serial feature negative (FN) and hippocampal-independent simple discrimination problems. Performance was then assessed following 7 days on ad libitum chow and after 10, 24, 40, 60, and 90 days of maintenance on WD, on ketogenic (KETO) diet which is high in saturated fat and low in sugar and other carbohydrates, or continued maintenance on chow (CHOW). Confirming and extending previous findings, diet-induced obese (DIO) rats fed WD showed impaired FN performance, increased BBB permeability, and increased fasting blood glucose levels compared to CHOW controls and to diet resistant (DR) rats that did not become obese when maintained on WD. For rats fed the KETO diet, FN performance and BBB integrity was more closely associated with level of circulating ketone bodies than with obesity phenotype (DR or DIO) with higher levels of ketones appearing to provide a protective effect. The evidence also indicated that FN deficits preceded and predicted increased body weight and adiposity. This research (a) further substantiates previous findings of WD-induced deficits in hippocampal-dependent feature negative discriminations, (b) suggests that ketones may be protective against diet-induced cognitive impairment, and (c) provides evidence that diet-induced cognitive impairment precedes weight gain and obesity.

An enormous amount of research has been aimed at identifying biological and environmental factors that are contributing to the current global obesity pandemic. The present paper reviews recent findings which suggest that obesity is attributable, at least in part, to a disruption of the Pavlovian control of energy regulation. Within our framework, this disruption occurs when (a) consumption of sweet-tasting, but low calorie or noncaloric, foods and beverages reduces the ability of sweet tastes to predict the postingestive caloric consequences of intake and (b) consuming diets high in saturated fat and sugar (a.k.a., Western diet) impairs hippocampal-dependent learning and memory processes that are involved with the use of interoceptive “satiety” signals to anticipate when food and eating are not followed by appetitive postingestive outcomes. The paper concludes with discussion of a “vicious-cycle’ model which links obesity to cognitive decline.

The use of high-intensity sweeteners has been proposed as a method to combat increasing rates of overweight and obesity in the human population. However, previous work with male rats suggests that consumption of such sweeteners might contribute to, rather than ameliorate, weight gain. The goals of the present experiments were to assess whether intake of high-intensity sweeteners is associated with increased food intake and body weight gain in female rats; to evaluate whether this effect depends on composition of the maintenance diet (i.e., standard chow compared to diets high in energy, fat and sugar [HE diets]); and to determine whether the phenotype of the rats with regard to propensity to gain weight on HE diets affects the consequences of consuming high-intensity sweeteners. The data demonstrated that female rats fed a low-fat, standard laboratory chow diet did not gain extra weight when fed yogurt dietary supplements sweetened with saccharin compared to those fed glucose-sweetened dietary supplements. However, female rats maintained on a “Westernized” diet high in fat and sugar (HE diet) showed significant increases in energy intake, weight gain and adiposity when given saccharin-sweetened compared to glucose-sweetened yogurt supplements. These differences were most pronounced in female rats known to be prone to obesity prior to the introduction of the yogurt diets. Both selectively-bred Crl:OP[CD] rats, and outbred Sprague-Dawley rats fed an HE diet showing high levels of weight gain (DIO rats) had increased weight gain in response to consuming saccharin-sweetened compared to glucose-sweetened supplements. However, in male rats fed an HE diet, saccharin-sweetened supplements produced extra weight gain regardless of obesity phenotype. These results suggest that the most negative consequences of consuming high-intensity sweeteners may occur in those most likely to use them for weight control, females consuming a “Westernized” diet and already prone to excess 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.