Animal models have provided insight into the physiology of weight regulation, including the hormonal and neurological communication between adipose tissue, the gut, and the brain. Adipocyte hormones, such as leptin, and gut hormones, such as ghrelin, control meal-related food intake and energy expenditure through mechanisms that include direct binding to receptors in the brain stem and brain, and by altering afferent vagal signaling. Recent imaging studies in humans recording brain responses to visual and gustatory food stimuli have consistently demonstrated involvement of dopaminergic pathways traditionally linked with reward motivation. With the discovery of leptin receptors within these pathways, a more integrated model of central nervous system control of food intake is emerging. Most of the imaging reports to date, however, have been cross-sectional studies that have compared obese to lean subjects. Only a few have measured brain responses to changes in levels of hormones involved in weight regulation, such as leptin, and only one studied patients after weight loss. Because of counter regulatory hormonal control, sustained weight loss is difficult to achieve in obese subjects despite intensive behavioral strategies. Bariatric surgery, however, achieves meaningful sustained weight loss, but the mechanisms for this are poorly understood. Thus, the overall goal for this project is to bring together clinical scientists with expertise in brain imaging and the physiological and behavioral control of food intake to better understand the role and interaction of changes in the sensitivity of the brain to hormonal signaling and response to external food stimuli following bariatric surgery. Subjects about to undergo either gastric bypass, gastric banding, or a low-calorie diet weight loss program will complete fMRI paradigms assessing BOLD activation of brain reward circuitry in response to food intake and food images under three different infusion conditions: leptin, ghrelin, and saline. They will also complete measures of body composition, visual analog scores for hunger and satiety, and adlibitum food intake. Participants will then return two more times after surgery to repeat this assessment protocol to determine if these bariatric procedures differentially impact BOLD response of reward circuitry to hormonal and food stimuli and whether this responsivity predicts subsequent weight loss. Finally, subgroups with polymorphisms of the dopamine D2 receptor and those with persistent binge eating behavior are hypothesized to be less responsive to effects of hormonal manipulation on brain fMRI response, to surgically induced weight loss, and will be more likely to regain weight during long-term follow-up. This project will provide new insights into mechanisms leading to sustained weight loss that involve brain centers regulating body weight and attempt to identify subgroups that are responders or non-responders following bariatric surgery.
Obesity is a leading cause of morbidity and mortality in America. Bariatric surgery is currently the most effective sustained weight-loss intervention for severely obese subjects, but the underlying mechanisms for this, especially the role of brain sensitivity to hormones involved in weight regulation and brain responsiveness to food stimuli, are not known. The study proposed here will advance our understanding of changes in brain reward circuitry signaling in response to bariatric surgery, may yield new insight into the causes of, and alternative treatments for, subjects who are overweight or obese, and attempt to identify subgroups who are likely to respond to surgical treatment of obesity, which would inform clinical decision making regarding appropriate candidates for bariatric surgery among the severely obese.
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| Purnell, J Q; Klopfenstein, B A; Stevens, A A et al. (2011) Brain functional magnetic resonance imaging response to glucose and fructose infusions in humans. Diabetes Obes Metab 13:229-34 |
| Klopfenstein, Bethany J; Purnell, Jonathan Q (2011) Comparison of the Freestyle Lite™ blood glucose monitoring system to the yellow springs instruments glucose oxidase analyzer for use during glucose clamp studies in nondiabetic subjects undergoing magnetic resonance imaging. J Diabetes Sci Technol 5:827-8 |
