Minutes of the Columbia University Seminar on Appetitive Behavior(#529)Date: October 1st, 2009 Seminar Title: "Gustatory reward in rat models of obesity and gastric bypass surgery" Speaker's Name and Affiliation:
Chair: Harry R. Kissileff, Ph.D. Rapporteur: Kathleen L. Keller, Ph.D. Attendees and their Affiliation:
Summary: (Prepared by the Speaker) Obesity is endemic in the United States. Obesity increases the risk of multiple medical conditions, including type 2 diabetes. Although the etiology of obesity is complex, over-consumption induced by the high palatability of the modern diet and individual differences in responsivity to palatability may contribute to obesity. Recent studies have suggested that the sensory and hedonic properties of sweet and fat vary with body mass index. Imaging studies have shown differential brain activation in lean and obese subjects in response to anticipation and consumption of palatable meals. Diets rich in highly preferred foods (carbohydrates and fat) can establish obesity also in animals. Multiple genetic rat models of obesity representing different aspects of human obesity exist. As a result of obesity epidemic, Roux-en-Y gastric bypass surgery (GBS) has become the fastest growing surgical procedure in the country. In addition to restricting food intake, GBS appears to promote satiety. After GBS, many patients note that they are not "hungry all the time" and can better resist palatable foods. Our recent survey revealed changes in the way sweet meals taste to patients after GBS. This clinical observation suggests that GBS actually reduces appetite and the appeal of tasty meals. However, it remains unclear why the motivational system fails to drive patients to compensate with increased meal frequency and to favor calorie-dense foods in response to massive weight loss. Similar to improvements in blood glucose levels, changes in eating habits occur rapidly after the surgery, suggesting that blood-borne factors released from the gut may play a role. The talk reviewed recent and ongoing studies in the Hajnal lab testing the hypothesis that overeating in obesity and the success of bariatric surgery in reducing appetite are related to altered gustatory reward. They then performed single neuron extracellular recording in the PBN, the second central taste relay in the rats, to assess sucrose concentration responses in lean and obese rats. These studies demonstrated that processing of sucrose-evoked activity in the PBN is altered in the Otsuka Long Evans Tokushima Fatty (OLETF) rats that develop obesity due to chronic overeating and express increased avidity to sweet. Compared with lean controls, taste neurons in OLETF rats had reduced overall sensitivity to sucrose and altered concentration responses: decreased responses to lower and augmented responses to higher concentrations. The decreased sensitivity to sucrose was specific to NaCl-best neurons that also responded to sucrose, but the concentration effects were carried by the sucrose-specific neurons. Collectively, these findings support the hypothesis that the PBN enables taste stimuli to engage the reward system and, in doing so, influences food intake and body weight regulation. Obesity, in turn, may further alter the gustatory code via forebrain connections to the taste relays or hormonal changes consequent to weight gain. A recent study investigated effects of GBS or sham-operation (SH) on body weight, glucose tolerance, behavioral and neuronal taste functions in the obese OLETF rats and lean controls LETO. OLETF-GBS rats lost body weight (-26%) and demonstrated improved glucose tolerance. They also expressed a reduction in 24-h 2-bottle preference for sucrose and decreased 10-s lick responses for sucrose (0.3M through 1.5M) compared to OLETF-SH or LETO-GBS. A similar effect was noted for other sweet compounds but not for salty, sour or bitter tastants. In lean rats, GBS did not alter responses to any stimulus tested. Extracellular recordings from 170 taste-responsive neurons of the PBN revealed a right-ward shift in concentration-responses to oral sucrose in obese compared to lean rats. These effects were reversed by GBS, and neural responses in OLETF-GBS were statistically not different from those in any LETO groups. These findings confirm obesity-related alterations in taste functions and demonstrate the ability of GBS to alleviate these impairments. In obese patients secretion of intestinal hormones that signal satiety like glucagon-like peptide-1 (GLP-1) and Peptide YY (PYY) are diminished. In addition to its anti-diabetic effects, GLP-1 reduces appetite and food intake. Dr. Hajnal and his surgeon collaborator, Dr. Cooney found that GBS alleviates these deficits and increases post-meal GLP-1 levels in the blood of obese patients and rats. Based on these observations they hypothesized that increased GLP-1 release after GBS helps to curb appetite by reducing the consumption of sweet tasting foods. These effects may occur in brain areas that sense taste, generate food reward (pleasure of eating), or both. To test this idea we examined sweet taste preferences in lean and obese rats that were treated with a GLP-1 analogue Exendin-4 (EX-4) for a week. Another experiment was carried out in anesthetized rats using recording electrodes put in the brain areas that are activated by taste or food reward while directly administering GLP-1 to the neurons. They found that the obese rats were less sensitive to the effects of the sweet preference reducing effect of the drug than the lean rats, but only when sucrose was ingested in larger amounts for an extended period. The taste effects of the treatment, however, appeared to be effective even in the obese rats. In the electrophysiology studies they found neurons in both the pontine taste relays and the dopamine neurons of the brain reward area that changed their activities in response to locally applied minute amounts of GLP-1. Collectively, these findings demonstrate that taste reward functions are altered in obesity and following GBS. In addition to peripheral targets, the underlying mechanism may involve direct action of GLP-1 on central taste neurons as well as dopamine neurons within the reward system. Research examining the effects of obesity, GBS and intestinal hormones on eating behavior could result in the development of more effective medical treatments for obesity. Discussion: Q. You might want to point out that in humans, most gastric bypass surgeries are done laproscopically.
Q. Is there much reflex from the small bowel to the duodenum?
Q. What is the measure of taste perception?
Q. There have been studies looking at taste receptors pre- and post- surgeries. Are you going to report those?
Q. Does anyone complain about a change in smell? There are insulin receptors in the olfactory system.
Q. Is this preference or acceptance?
Q. If I remember, the OLEFT rats do not get obese till around 8 weeks. Is this increased operant responding to sucrose due to obesity, or inherent in the rat?
Q. If you create diet induced obesity in the lean rats, would you expect them to look more like the OLEFT rats in terms of operant responding to sucrose?
Q. In humans, most dopamine antagonists increase food intake. Can you explain why you don't see that in animals?
Q. In these experiments, is the volume of intake clamped?
Q. That is dorsal striatum dopamine, right?
Q. What time and conditions were basal measurements taken under?
Q. Can you explain how you stimulated dopamine?
Q. What do you mean by "capacity" of vesicular dopamine pool?
Q. Is this test done under the influence of a dopamine reuptake blocker?
Q. When Volcow talks about dopamine in human obesity, they analogize it to substance abuse (and the result of decreased D2 receptor density). How does this compare to your theory?
Q. In some of the dopamine literature, there is a comparison to taste reward, particularly in response to glucose taste.
Q. Is this sham-fed sucrose?
Q. Can you access sucrose sensitivity before rats become obese?
Q. They are drinking more of the sweetened / sucrose to get to the same dopamine response?
Q. Are you doing oral glucose tolerance tests?
Q. Do you know if after surgery the cephalic phase insulin release is in tact?
Q. In rats that have gastric bypass surgery (GBS), is total intake of water higher or lower?
Q. Were the animals that had GBS na?ve to sucrose?
Q. What is the sham surgery?
Q. This is endogenous GLP-1 in the brain. There's no evidence that GLP-1 crosses the blood brain barrier?
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