It must be my metabolism: Metabolic control of mind

• Main Author: Dana M Small
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2014-07-01
• Series: Frontiers in Integrative Neuroscience
• Subjects: Reward; flavor; food cues; sugar; Food metabolism; Sweetness
• Online Access: http://journal.frontiersin.org/Journal/10.3389/conf.fnint.2015.03.00002/full

For millennia it was advantageous to overeat whenever food was available in order to create reserves of energy for likely future episodes of famine. Neural circuits thus evolved to promote eating in the absence of hunger when cues signaling food availability were encountered. In today’s food environment, this once adaptive behavior may fuel the obesity epidemic. An oft-used index of one’s propensity to eat in the absence of hunger is “food cue reactivity”. How “reactive” one is to a food cue can be assessed in a variety of ways. Food intake can be measured subsequent to initial exposures to the sight, taste or smell of a palatable food. Not surprisingly, overweight and obese individuals are more likely to eat or to eat more than their lean counterparts when presented with food cues (1). Measuring brain response to food cues can also assess food cue reactivity. Heightened responses in dopamine source and target regions are associated with increased food consumption (2-5), weight gain (6-9), and poor outcomes in weight loss programs (10). Paralleling the behavioral data, overweight and obese individuals also show heightened responses to food cues, as do individuals at risk for overeating (11-14). Despite the reliable relationship between brain response to food cues and obesity the mechanism by which food cues drive brain response is unknown. To identify factors that regulate food cue reactivity in humans we have employed a flavor nutrient conditioning protocol in which associations are formed between a novel flavor and calorie content. In the rodent model, it is well established that pairing a novel flavor with intra-gastric infusion of glucose conditions a strong preference for that flavor when later consumed in the absence of calories (15). This implies that a peripheral signal generated by the glucose infusion is critical for flavor preference formation. Recent work also performed in the rodent model demonstrates that there is a close relationship between the reinforcing potency of sugared solutions and the metabolic effects that follow their consumption (16, also see the abstract of I. de Araujo). We therefore hypothesized that metabolic response provides the critical signal necessary to condition preference. To test this prediction in humans we designed a flavor nutrient conditioning study in which participants first rated their liking for novel flavored beverages and then, over a three week-long conditioning protocol, alternately ingested one of the flavored beverages with 112.5 kcal from maltodextrin, a tasteless and odorless polysaccharide that breaks down into glucose, and another flavored beverage with no calories added. Plasma glucose was measured before and after each of the drinks’ consumption as a proxy measure of metabolic response, assuming that glucose oxidation depends upon the level of circulating glucose. For each participant flavor-calorie pairings were held constant but the identity of the conditioned flavors were counterbalanced across participants. Following the exposure phase, participants’ liking of, and brain responses to, non-caloric versions of the flavors were assessed. We predicted that change in plasma glucose produced by beverage consumption during the exposure sessions would be associated with neural responses in dopamine source and target regions to the calorie predictive flavor. As predicted, response in the ventral striatum and hypothalamus to the calorie-predictive flavor (CS+) vs. non the noncaloric-predictive flavor (CS-) was strongly associated with the changes in plasma glucose levels produced by ingestion of these same beverages when consumed previously either with (CS+) or without (CS-) calories (17). Specifically, the greater the increase in circulating glucose occurring post ingestion of the beverage containing 112.5 kcal from maltodextrin versus the noncaloric drink, the stronger was the brain response to the CS+ compared to the CS- flavor. Importantly, because each participant ingested the same caloric dose during conditioning, changes in plasma glucose depended upon individual differences in glucose absorption/metabolism. Therefore, these findings provide indirect, and yet convincing, support for our hypothesis that glucose metabolism regulates response to calorie-predictive flavors in brain reward circuits. We can therefore conclude that, at least for carbohydrates, responses to calorie predictive food cues reflect the learned association between the cue and its ability to result in a change in blood glucose. This finding has important implications for understanding how the modern food environment promotes weight gain. Carbohydrates now come in forms and doses not experienced during our evolutionary past. Not only are calories increased, but the way in which they are metabolized differs. For example, calories ingested in liquid form are trafficked through the gut faster than solids (e.g. 18). Might this influence metabolic regulation of reward circuits? Certainly it stands to reason that larger loads delivered more quickly to the circulation might increase the metabolic impact and hence more efficiently engage reward circuits to enhance food cue reactivity and promote eating in the absence of hunger. In summary, our result indicates that, as in the rodent model, metabolic response drives the reinforcement potency of carbohydrates and regulates food cue reactivity. We conclude that not only are modern foods more caloric, but in addition their increased metabolic impact drives reward circuits and may therefore promote intake by enhancing food cue reactivity. Our finding further suggests that metabolic regulation of reward circuits may differ in individuals with altered glucose metabolism, such as type II diabetes, offering a potential mechanism by which they become susceptible to weight gain.