Is PYY a future therapeutic peptide for the treatment of obesity?
Peptide YY (PYY) was first discovered to play a role in digestion in 1985 when it was found to be secreted from the the cells of the small intestine in response to food consumption, the proportion secreted related to the calorie content of the meal. Studies in animals had found that administration of PYY caused the gastrointestinal tract (GI) to slow down its peristaltic motions. The role of PYY was not known and so it was concluded that PYY acted to control motor and secretary functions of the GI tract (Adrian et al. 1985).
PYY is currently at the centre of a hotly contested debate in obesity research regarding its use as a potential therapy for obesity. This debate has become a rather controversial one with two very different opinions from different laboratories. One laboratory believing that PYY is indeed an inhibitor of appetite and the other laboratory unable to replicate the success of the other sides’ results. The debate began in 2002 when Batterham et al (2002) found that the peripheral administration of PYY resulted in a significant decrease in food intake. These researchers found that PYY travelled in the blood to the hypothalamic arcuate nucleus where it acted as an agonist of one of the NPY receptors, called the Y2 receptor. The Y2 receptor is a pre-synaptic inhibitory receptor that blocks the orexigenic effects of the NPY/AgRP neurones. Upon PYY binding to the Y2 receptor, appetite was inhibited (see Figure 1) and so they concluded that chronic administration of PYY to inhibit appetite could be a candidate as a potential anti obesity therapy. These results were found to be consistent in human trials, inhibiting appetite for up to 12 hours. These results sparked a real excitement about the possible use of PYY as a therapy against obesity.
Mode of action
Batterham et al (2002) thought that PYY acted by inhibiting the NPY neurones resulting in a decrease in the release of the inhibitory neurotransmitter GABA. As a result the POMC neurones are free from inhibition and so can release alpha MSH, a powerful inhibitor of appetite.
Figure 1: Schematic showing PYY acting on the NPY neurones causing activation of the POMC neurones
The excitement of Batterham et al’s (2002) results was short lived however as subsequent investigators were unable to replicate their results (Tschoep et al, 2004, Gura, 2004). In an effort to support Batterham's findings, many investigators collaborated and went to great lengths to ensure they made every effort to gain accurate results, using over 1000 mice from 12 different laboratories. Tschoep et al (2004) used human and rodent PYY, PYY from various suppliers, and ensured all rodents were habituated to their surroundings to prevent stress. Stress can also cause the inhibition of appetite so they ensured a stress response did not affect their results. In the end, however, they concluded that there was no evidence that PYY caused a reduction in food intake, and so therefore, could not be considered a prime candidate as a drug to fight obesity.
Batterham et al (2004) responded to the findings by Tschoep et al (2004) implying that the discrepancy in the results was due to a stress response. Other factors were not considered as well by Tschoep et al (2004), the concentration of PYY in the blood after peripheral administration was not measured and so there was no way of knowing if circulatory levels were high enough to cause a reduction in food intake as observed by Batterham et al (2002). Tschoep et al's results did also not explain why Batterham found changes in the mRNA expression of NPY, and why, when a different NPY Y2 receptor agonist was used, reduced food intake was again found. Tschoep et al also used a different protocol from Batterham et al, not administering the PYY after fasting therefore PYY may be already raised in the animal.
In support of Batterham et al (2002), other investigators have found PYY to be an inhibitor of appetite. Halatcher et al (2004) found a reduction in food intake when PYY was given peripherally, but only in rats that had fully acclimatised to their surroundings and so were not stressed. However they only found PYY to be effective for 4 hours post injection. They concluded that PYY’s effects on food intake were short term and so discrepancies found by other investigators could be due to them missing PYY’s effects by measuring too long after injection. They also stated that without proper habituation of the animals to their surroundings, any reduction in appetite by PYY could be masked by the effects of stress. It was also found that PYY may not inhibit appetite by its effects on the arcuate POMC neurones as mice lacking the alpha MSH MC4 receptor (so not affected by alpha MSH) also show a reduction in food intake after administration of PYY similar comparable to wild type mice, implying that the MC4 receptor is not essential for the PYY mode of action. The conclusions from this data appear to be that in support of Batterham et al (2002), PYY does cause a reduction in food intake but it does not do this through acting on the MC4 receptor, therefore making it distinct from other peripheral peptides like ghrelin and leptin.
So how does PYY exert its anorexigenic effects, as Batterham et al (2002) found that POMC neurones were activated by PYY yet the MC4 receptor does not appear necessary (Halatcher, et al 2004), perhaps PYY acts on other melanocortin receptors. This idea will need investigating in the future.
To fully determine PYY’s role in satiety should we not first determine its physiological role?
Recent experiments on PYY have found that at physiological doses, PYY does not induce the feeling of fullness, and therefore decrease food intake, but at pharmacological doses it does (Degen et al, 2005, Beglinger & Degen, 2006). It appears therefore that PYY's primary role may not be that of a satiety factor at physiological concentrations, so what then is its primary role?
The criteria for classifying a satiety signal are (Beglinger & Degen, 2006):
- It must reduce the size of a meal
- This must then be reversed upon application of a receptor antagonist or if the signal is removed
- The signal must not result from illness
- Secretion must be induced by eating and ingesting.
At pharmacological doses, PYY fits all of these criteria except point 2 because unfortunately there is currently no known specific antagonist for the NPY Y2 receptor so the mechanism of PYY cannot be fully explored. If an antagonist were available investigations could determine if PYY was acting centrally as thought by Batterham et al (2002) or peripherally where it could act in the gut, stimulating the vagal afferents to decrease appetite.
PYY is involved in the regulation of appetite but perhaps only when given at doses higher than those naturally occurring at physiological levels upon food ingestion. Firmly identifying the physiological role of PYY is necessary to assess its importance in appetite regulation, and from there, as a candidate for an anti obesity drug. Until we can find an antagonist of the NPY Y2 receptor, PYY’s primary role may remain elusive.
Conclusions and Final thoughts
Batterham et al. 2002. Gut Hormone PYY physiologically inhibits food intake. Nature. 418. pp650-654 - The first evidence of a role for PYY in inhibiting appetite.
Tschoep et al. & Batterham et al. 2004. Physiology: Does gut hormone PYY decrease food intake in rodents? Nature. 430. pp1-4 - The contradictory research as found by Tschop et al. followed by a reply from Batterham