Neural Regulation of Eating: Taste and Food Reward Functions in Animal Models of Obesity, Type-2 Diabetes, and Gastric Bypass Surgery

My quest is to understand the relationship between neural circuitries that monitor internal homeostatic variables and process information from multiple sensory systems to form a motivational state. This, in turn, facilitates appropriate behavioral responses. To study this complex neural function, my research examines the prototype of all motivated behaviors, feeding and its pathologies, eating disorders and obesity. Specifically, the research in my laboratory focuses on the integration of orosensory, viscerosensory, and metabolic signals relevant to the motivational control of meal size, meal patterns, food selection, and the maintenance of body weight.

I have institutionally and extramurally funded independent but highly collaborative research programs in the following areas:

1. the interaction between metabolic events, orosensory factors, and central dopamine functions that are relevant a) to the initiation and termination of eating and b) to the development of long term feeding patterns;
   


2. the neural regulation of meal size and food preferences during the development of type-2 diabetes;
   


3. the central taste and motivational processes in obesity;


4. the effects of gastric bypass surgery on taste and food reward functions in animal models of obesity.
   

In the first research area, we are investigating the effects of oral sucrose stimulation on the mesoaccumbens dopamine system critical to motivation and the neural mechanisms that change gustatory coding during satiation. In addition, we have developed a bingeing-type rat model for studying long-term effects of palatable meals on the development of feeding patterns. We have demonstrated that, when rats are food restricted, timed access to a preferred stimulus (a scenario that is similar to snacking in restricted eaters) leads to neural plasticity in the dopamine systems, and this effect is mediated, at least in part, by the orosensory stimulation of savory meals. More recently, using brief low-dose treatment with methylphenidate (Ritalin), we demonstrated that this effect was dopamine dependent. These data also suggested a potential therapy to reduce bingeing on palatable snacks without affecting intake of regular meals.

The second and third research areas focus on the mechanisms that lead to obesity and type-2 diabetes by altering central motivational systems. One of these approaches uses a genetically mutant obese rat model, the novel OLETF strain that lacks the cholecystokinin-1 receptor. These receptors mediate the satiation effect of cholecystokinin released during a meal, and in turn play a role in the termination of eating. The OLETF rats lacking this signal are hyperphagic, obese, and gradually develop non-insulin-dependent diabetes mellitus (type-2 diabetes). In both the OLETF rats and humans, an increased preference for and intake of highly palatable foods (i.e. sweet and fatty) characterize the development of type-2 diabetes. These foods are also high in calories and usually lead to obesity. Thus, it is plausible that a dysregulation in the neuronal substrate underlying feeding motivation contributes to these consequences. In fact, our recent studies using behavioral, nutritional, and pharmacological approaches have demonstrated an increased appetitive, consummatory, and operant responsiveness of the prediabetic OLETF rats to highly palatable sucrose solutions. Furthermore, these effects were differentially sensitive to administration of dopamine receptor antagonists. A recent project extends these investigations to non-mutant, high-fat diet-induced obese rats, and also to non obese rats that are chronically exposed to a high-fat diet.

The fourth research area is a translational collaboration with the Cooney lab in the Department of Surgery. It was designed to develop an animal model that can be used to investigate the effects of Roux-en-Y gastric bypass surgery on the neural regulation of appetite, food choice, and related eating variables. Multiple experiments are in progress testing the hypothesis that gastric bypass surgery alters preference-aversion functions by altering the neural processing of taste information. From a clinical perspective this research aims to understand the neural factors that facilitate long-term maintenance of weight loss in patients undergoing weight management.
Overall, the benefit of our work is to understand the basic mechanisms of alterations in the taste, and reward-related neural processes produced by the feedback effects of food under physiological and pathological conditions. Knowledge of these mechanisms will help to combat pathological eating behaviors (e.g. food cravings, bingeing) and diet-induced obesity.