Translational analyses of ingestive behavior after gastric bypass

Roux-en-Y gastric bypass (RYGB) decreases appetite, caloric intake, glycemia, and body weight, all of which are maintained long-term. It is controversial whether, after RYGB, patients choose to eat less highfat and sugary foods in favor of lower energy dense alternatives. If true, this could conceivably contribute to improved glycemia and body weight. Disparities among studies on food selection and intake are likely due to the almost complete reliance on self-reported food intake which is vulnerable to inaccuracy. This controversy can best be resolved by complementing existing findings with direct measures of target behaviors in humans that can also be applied to animal models and vice-versa. There has been virtually no published work involving direct measures of changes in food selection after RYGB in humans, and the few studies involving animal models have had limited scope. Our first objective with this unique US-Ireland R&D Partnership Program is to extend the findings from our ongoing collaboration suggesting that RYGB alters food preferences without ostensibly changing food palatability. RYGB in rats decreases the preferential selection of sweet and fatty foods and fluids, but does not consistently shift taste-guided concentration-dependent responding during brief-access trials with sucrose, nor does it reduce ratings of ideal sweetness in patients. Studies on the impact of RYGB on appetitive behavior in rodents and humans have produced mixed findings. Thus, it remains unclear whether there are fundamental shifts in the palatability of high-fat and sugary foods after RYGB or simply a decrease in the motivation to ingest them. Moreover, learning processes are implicated because changes in food preferences appear to progress with experience.

Such changes in food selection alone have been postulated to benefit patients with obesity and/or Type 2 diabetes mellitus (T2DM); and this may be an under-investigated means by which RYGB improves maintenance of body weight and glycemic control. We propose to use direct measures in both rodents and humans after RYGB to test the hypothesis that the selection and intake of foods varying in fat content and glycemic index, as well as the pattern of ingestion within and across meals, changes in a manner that leads to beneficial outcomes on body weight. Moreover, we will determine whether progressive modulation of food preference after RYGB that occurs in the rat model and putatively occurs in patients is due to shifts in palatability (taste aversion, conditioned or unconditioned) or due to learned adjustments in feeding behavior that minimize negative visceral signals during meals (conditioned avoidance). We aim to disambiguate these possibilities, because doing so has potential to define and guide the search for peripheral signals and neural circuits underlying the hypothesized changed behavior and can inform the development of safer surgical and/or nonsurgical therapeutic interventions as well as offer insight into how benefits can be maintained long-term. The physiological mechanisms underlying changes in feeding, weight loss, and glycemic control after RYGB remain contested. Multiple gut hormones have exaggerated responses after RYGB and may be the most promising lead. Test meal size after RYGB has been shown to increase when the pleiotropic gut hormone responses are attenuated by Octreotide (a somatostatin analogue. GLP-1, one of more extensively studied gut hormones, is known to increase after RYGB and its analogues are currently used to pharmacologically treat obesity and T2DM. Among its effects, GLP-1 reduces food intake. However, whether such manipulations affect food selection after RYGB remains to be tested. Therefore, we will test the effects of Octreotide on food selection in both humans and rats after RYGB. Further, in our rat model, we will assess the effects of chronic delivery of Octreotide, as well as Exendin-9 (Ex-9), a specific GLP-1R antagonist, on progressive changes in intake of select foods observed after RYGB.

Award Date
20 May 2016
Award Value
€349,999
Principal Investigator
Professor Carel le Roux
Host Institution
University College Dublin
Scheme
US-Ireland R&D Partnership Awards