They claim, in this week's Nature, that it travels to the brain's hypothalamus, where it shuts down nerves that trigger eating.
Volunteers injected with the hormone, called PYY3-36, helped themselves to one-third less food from a free buffet, Dr Stephen Bloom of Imperial College, London, and his colleagues discovered, and ate less for up to 12 hours.
Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus of the brain.
Within the arcuate nucleus, which is accessible to peripheral hormones, these 2 distinct subsets of neurons control food intake by acting in opposing manners to one other.
'Accelerator' neurons produce NPY, which acts in the brain to stimulate feeding, while adjacent 'braking' neurons produce melanocortin peptides. These act on the same areas of the brain as NPY, but inhibit eating.
During weight loss for example, NPY-expressing neurons are activated and melanocortin-producing neurons are inhibited - responses that stimulate eating and promote the recovery of depleted fuel stores when sufficient food becomes available.
Within the NPY system is a highly expressed presynaptic receptor named Y2R (NPY Y2 receptor).
A known agonist of Y2R is peptide YY3-36 (PYY3-36), a gut-derived hormone that is released post-prandially in proportion to the calorific intake.
This hormone, which is made by endocrine cells lining the distal small bowel and colon, rises in the blood after eating and remains high between meals.
Dr Bloom and his colleagues therefore investigated the effects of peripheral administration of PYY3-36 on feeding.
Initially using rodent studies, intra-peritoneal injection of PYY3-36 was shown to reduce both food intake and weight gain in rats.
Studies in Y2r-null mice also showed that the hormone could inhibit food intake, but no longer had an anorexic action, suggesting that PYY3-36 may require Y2R for mediation of this effect.
Using a combination of electrophysiological and hypothalamic explant studies, the research group were able to show that PYY3-36 can directly influence hypothalamic circuits, resulting in co-ordinate changes in the action of adjacent pro-opiomelanocortin and NPY neurons.
In addition, PYY3-36 administered directly into this region of the brain was also shown to reduce food intake.
12 healthy fasted, non-obese volunteers (six men and six women: mean age, 26.7 ±0.7 years; BMI, 24.6 ±0.94 kg m-2) were then recruited to examine the effects of PYY3-36 in humans.
| PYY3-36 infusion reduced calorie intake by a third |
| Nature |
The volunteers were infused with PYY3-36 (0.8 pmol per kg (body weight) per min) or saline for 90 minutes, in a double-blind, placebo-controlled crossover study.
PYY3-36 plasma concentrations were found to increase from a mean basal concentration of 8.3 ±1.0 pM to a maximum of 43.5 ±3 pM during the
PYY3-36 infusion and mimicked post-prandial concentrations.
After infusion, PYY3-36 concentrations returned to basal levels within 30 minutes, but resulted in a significant decrease in hunger scores, as assessed by a visual analogue scale.
2 hours after terminating the infusion, subjects were offered an excess free-choice buffet meal, such that all appetites could be satisfied. Food and water were weighed pre- and post-prandially, and caloric intake was calculated.
The researchers found that in the PYY3-36-infused subjects, calorie intake was reduced by more than a third compared with saline controls (36 ±7.4%).
However, there was no effect on fluid intake and no difference in sensations of fullness or nausea reported by the volunteers.
PYY3-36 administration also had no effect on gastric emptying, as estimated by the paracetamol absorption method, or on plasma glucose, plasma leptin or insulin.
Analysis of food diaries kept by the volunteers showed a significant inhibition of food intake in the 12-hour period after the PYY3-36 infusion (saline group, 2,205 ±243 kcal versus PYY3-36 group, 1,474 ±207 kcal).
Over the 12-hour to 24-hour period however, food intake between the two groups was virtually identical.
Overall there was a 33% decrease in cumulative total calorie consumption in the 24-hour period after the PYY3-36 infusion.
Commenting on the results of the studies, Dr Bloom said they showed that post-prandial concentrations of PYY3-36 inhibit food intake in both rodents and man for up to 12 hours, suggesting a role for PYY3-36 in 'longer term' regulation of food intake.
"It's what stops you having the third helping," he joked.
This contrasts with previously characterized gut-derived 'short-term' satiety signals such as cholecystokinin1, the effects of which are relatively short-lived.
Continuing, Dr Bloom said, "The failure of PYY3-36 to inhibit food intake in the Y2r-null mice provides further evidence that PYY3-36 reduces food intake through a Y2R-dependent mechanism."
"Our results suggest that a gut-hypothalamic pathway that involves postprandial PYY3-36 acting at the arcuate Y2R has a role in regulating feeding."
Researchers hope that the PYY3-36 system may provide a therapeutic target for the treatment of obesity.
Drugs mimicking the peptide hormone and taken before mealtimes might work to curb appetite and help fight weight gain.
"If we are to combat the global obesity epidemic, such breakthroughs are urgently needed," said Michael Schwartz of the University of Washington in Seattle, USA, in an accompanying News and Views article.