The responses of the gut hormone peptide YY (PYY) to food were investigated in 20 normal-weight and 20 obese humans in response to six test meals of varying calorie content. Human volunteers had a graded rise in plasma PYY (R2 = 0.96; P < 0.001) during increasing calorific meals, but the obese subjects had a lower endogenous PYY response at each meal size (P < 0.05 at all levels). The ratio of plasma PYY(1-36) to PYY(3-36) was similar in normal-weight and obese subjects. The effect on food intake and satiety of graded doses of exogenous PYY(3-36) was also evaluated in 12 human volunteers. Stepwise increasing doses of exogenous PYY(3-36) in humans caused a graded reduction in food intake (R2 = 0.38; P < 0.001). In high-fat-fed (HF) mice that became obese and low-fat-fed mice that remained normal weight, we measured plasma PYY, tissue PYY, and PYY mRNA levels and assessed the effect of exogenous administered PYY(3-36) on food intake in HF mice. HF mice remained sensitive to the anorectic effects of exogenous ip PYY(3-36). Compared with low-fat-fed fed mice, the HF mice had lower endogenous plasma PYY and higher tissue PYY but similar PYY mRNA levels, suggesting a possible reduction of PYY release. Thus, fasting and postprandial endogenous plasma PYY levels were attenuated in obese humans and rodents. The PYY(3-36) infusion study showed that the degree of plasma PYY reduction in obese subjects were likely associated with decreased satiety and relatively increased food intake. We conclude that obese subjects have a PYY deficiency that would reduce satiety and could thus reinforce their obesity.

Gastric bypass leads to the remission of type 2 diabetes independently of weight loss. Our hypothesis is that changes in bile flow due to the altered anatomy may partly explain the metabolic outcomes of the operation. We prospectively studied 12 patients undergoing gastric bypass and six patients undergoing gastric banding over a 6-wk period. Plasma fibroblast growth factor (FGF)19, stimulated by bile acid absorption in the terminal ileum, and plasma bile acids were measured. In canine and rodent models, we investigated changes in the gut hormone response after altered bile flow. FGF19 and total plasma bile acids levels increased after gastric bypass compared with no change after gastric banding. In the canine model, both food and bile, on their own, stimulated satiety gut hormone responses. However, when combined, the response was doubled. In rats, drainage of endogenous bile into the terminal ileum was associated with an enhanced satiety gut hormone response, reduced food intake, and lower body weight. In conclusion, after gastric bypass, bile flow is altered, leading to increased plasma bile acids, FGF19, incretin. and satiety gut hormone concentrations. Elucidating the mechanism of action of gastric bypass surgery may lead to novel treatments for type 2 diabetes.

ObjectivesRoux-en-Y gastric bypass (RYGB) has greater efficacy for weight loss in obese patients than gastric banding (BAND) surgery. We hypothesise that this may result from different effects on food hedonics via physiological changes secondary to distinct gut anatomy manipulations.DesignWe used functional MRI, eating behaviour and hormonal phenotyping to compare body mass index (BMI)-matched unoperated controls and patients after RYGB and BAND surgery for obesity.ResultsObese patients after RYGB had lower brain-hedonic responses to food than patients after BAND surgery. RYGB patients had lower activation than BAND patients in brain reward systems, particularly to high-calorie foods, including the orbitofrontal cortex, amygdala, caudate nucleus, nucleus accumbens and hippocampus. This was associated with lower palatability and appeal of high-calorie foods and healthier eating behaviour, including less fat intake, in RYGB compared with BAND patients and/or BMI-matched unoperated controls. These differences were not explicable by differences in hunger or psychological traits between the surgical groups, but anorexigenic plasma gut hormones (GLP-1 and PYY), plasma bile acids and symptoms of dumping syndrome were increased in RYGB patients.ConclusionsThe identification of these differences in food hedonic responses as a result of altered gut anatomy/physiology provides a novel explanation for the more favourable long-term weight loss seen after RYGB than after BAND surgery, highlighting the importance of the gut–brain axis in the control of reward-based eating behaviour.

Circulating levels of the gastric hormone ghrelin rise before and decrease after a meal. In normal-weight subjects, postprandial suppression of ghrelin is proportional to calories consumed. Obese individuals have lower fasting ghrelin levels; however, it is unclear whether the obese show normal postprandial suppression. This study aimed to compare postprandial ghrelin responses in normal-weight and obese subjects, using mixed macronutrient meals with varied fat and calorie content. Postprandial ghrelin response was measured in normal-weight insulin-sensitive subjects and obese insulin-resistant subjects, after six test meals with different fat and calorie content (250-3000 kcal). Increasing the calorie content of meals in normal-weight subjects progressively lowered nadir levels of ghrelin. The obese had lower fasting ghrelin levels, and the reduction after the consumption of all test meals was less than the normal-weight subjects. The lowest postprandial levels in the obese were no different to the nadir in normal-weight volunteers after 1000-, 2000-, and 3000-kcal meals. Thus, circulating ghrelin levels decreased in normal-weight subjects after mixed meals. Obese subjects demonstrated a much reduced ghrelin postprandial suppression. This reduced suppression may influence satiety, thus reinforcing obesity.

Context:The rate at which people eat has been suggested to be positively associated with obesity, although appetite and related gut hormones have not been measured. Objective:The objective of the study was to determine whether eating the same meal at varying speeds elicits different postprandial gut peptide responses. Design and Setting:This was a crossover study at a clinical research facility.Study Participants: Seventeen healthy adult male volunteers participated in the study. Intervention:A test meal consisting of 300 ml ice cream (675 kcal) was consumed in random order on two different sessions by each subject: meal duration took either 5 or 30 min. Main Outcome Measures:The postprandial response of the orexigenic hormone ghrelin and the anorexigenic peptides peptide YY and glucagon-like peptide-1 over 210 min was assessed. Visual analog scales for the subjective feelings of hunger and fullness were completed throughout each session.Results: Peptide YY area under the curve (AUC) was higher after the 30-min meal than after the 5-min meal (mean Ϯ SEM AUC 5 min meal: 4133 Ϯ 324, AUC 30 min meal: 5250 Ϯ 330 pmol/liter ⅐ min, P ϭ 0.004), as was glucagon-like peptide-1 AUC (mean Ϯ SEM AUC 5 min meal: 6219 Ϯ 256, AUC 30 min meal: 8794 Ϯ 656 pmol/liter ⅐ min, P ϭ 0.001). There was a trend for higher visual analog scale fullness ratings immediately after the end of the 30-min meal compared with immediately after the 5-min meal. There were no differences in ghrelin response.Conclusions: Eating at a physiologically moderate pace leads to a more pronounced anorexigenic gut peptide response than eating very fast. (J Clin Endocrinol Metab 95: 333-337, 2010)

With gastric bypass, type 2 diabetes can be improved and even rapidly put into a state of remission irrespective of weight loss. Improved insulin resistance within the first week after surgery remains unexplained, but increased insulin production in the first week after surgery may be explained by the enhanced postprandial GLP-1 responses.

RYGB leads to increased GLP-2 and mucosal crypt cell proliferation. Other gut hormones from l-cells remain elevated for at least 2 years in humans. These findings may account for the restoration of the absorptive surface area of the gut, which limits malabsorption and contributes to the long-term weight loss after RYGB.

The data indicate DJBL to be a promising treatment for obesity and type 2 diabetes, causing rapid improvement of glycemic control paralleled by changes in gut hormones.