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.

Our understanding of the physiological systems that regulate food intake and body weight has increased immensely over the past decade. Brain centres, including the hypothalamus, brainstem and reward centres, signal via neuropeptides which regulate energy homeostasis. Insulin and hormones synthesized by adipose tissue reflect the long-term nutritional status of the body and are able to influence these circuits. Circulating gut hormones modulate these pathways acutely and result in appetite stimulation or satiety effects. This review discusses central neuronal networks and peripheral signals which contribute energy homeostasis, and how a loss of the homeostatic process may result in obesity. It also considers future therapeutic targets for the treatment of obesity.

This study investigated the effect of subcutaneously administered oxyntomodulin on body weight in healthy overweight and obese volunteers. Participants self-administered saline or oxyntomodulin subcutaneously in a randomized, double-blind, parallel-group protocol. Injections were self-administered for 4 weeks, three times daily, 30 min before each meal. The volunteers were asked to maintain their regular diet and level of physical exercise during the study period. Subjects’ body weight, energy intake, and levels of adipose hormones were assessed at the start and end of the study. Body weight was reduced by 2.3 ± 0.4 kg in the treatment group over the study period compared with 0.5 ± 0.5 kg in the control group (P = 0.0106). On average, the treatment group had an additional 0.45-kg weight loss per week. The treatment group demonstrated a reduction in leptin and an increase in adiponectin. Energy intake by the treatment group was significantly reduced by 170 ± 37 kcal (25 ± 5%) at the initial study meal (P = 0.0007) and by 250 ± 63 kcal (35 ± 9%) at the final study meal (P = 0.0023), with no change in subjective food palatability. Oxyntomodulin treatment resulted in weight loss and a change in the levels of adipose hormones consistent with a loss of adipose tissue. The anorectic effect was maintained over the 4-week period. Oxyntomodulin represents a potential therapy for obesity.

Our knowledge of the physiological systems controlling energy homeostasis has increased dramatically over the last decade. The roles of peripheral signals from adipose tissue, pancreas, and the gastrointestinal tract reflecting short- and long-term nutritional status are now being described. Such signals influence central circuits in the hypothalamus, brain stem, and limbic system to modulate neuropeptide release and hence food intake and energy expenditure. This review discusses the peripheral hormones and central neuronal pathways that contribute to control of appetite.

Oxyntomodulin has recently been found to decrease body-weight in obese humans and may be a potential anti-obesity therapy. To determine whether oxyntomodulin alters energy expenditure, in addition to reducing energy intake, in ‘free-living’ overweight and obese volunteers. Randomized double-blind controlled cross-over trial. Community and hospital-based. Fifteen healthy overweight and obese men and women (age: 23–49 years, BMI: 25.1–39.0 kg/m²). All volunteers completed the study protocol. Four-day subcutaneous self-administration of pre-prandial oxyntomodulin, three times daily. Participants were advised to maintain their normal dietary and exercise regimen. (1) Energy expenditure, measured by indirect calorimetry and combined heart rate and movement monitoring; (2) energy intake, measured during a study meal. Oxyntomodulin administration reduced energy intake at the study meal by 128±29 kcal (P=0.0006) or 17.3±5.5% (P=0.0071), with no change in meal palatability. Oxyntomodulin did not alter resting energy expenditure; but increased activity-related energy expenditure by 143±109 kcal/day or 26.2±9.9% (P=0.0221); total energy expenditure by 9.4±4.8% (P=0.0454) and physical activity level by 9.5±4.6% (P=0.0495). A reduction in body weight of 0.5±0.2% was observed during the oxyntomodulin administration period (P=0.0232). Oxyntomodulin increases energy expenditure while reducing energy intake resulting in negative energy balance. This data supports the role of oxyntomodulin as a potential anti-obesity therapy.