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Amylin Pharmaceuticals Inc. San Diego, California 92121
Address all correspondence and requests for reprints to: Andrew A. Young, Vice President and Senior Research Fellow, Amylin Pharmaceuticals Inc., 9360 Towne Centre Drive, San Diego, California 92121. E-mail: andrew.young{at}amylin.com.
As drug candidates, peptide hormones are twice blessed. From their evolved purpose, they inherit an enhanced probability of biological effect. From the same evolutionary forge, they also inherit a low probability of toxic failure. With these hurdles overcome, the excitement surrounding the antiobesity potential of peptide YY (PYY) (1) and related peptides may be justified. PYY is cosecreted with glucagon-like peptide-1 (GLP-1), GLP-2, and oxyntomodulin, particularly in response to fat- and protein-containing meals (2), from intestinal L-cells. Recent interest in the predominant circulating species, PYY(3–36), stems from its potent inhibition of food intake in rats and humans (3, 4) and the therapeutic promise revealed from its benefits in animal models of obesity (5, 6) and diabetes (6).
But peptides can stumble. For example, unfavorably rapid degradation impeded use of native GLP-1 (7), and aggregation of human amylin compelled the development of an analog. Hormone resistance, as occurs with insulin, leptin (8), and glucose-dependent insulinotropic peptide (9), can also limit clinical application such that clinically meaningful effects can be achieved only with doses too large to be practically or economically delivered. Hormone resistance typically occurs in a situation of hormonal excess but not in situations of comparative deficiency. In defining obesity as a PYY-deficient state and showing here and elsewhere that its effect is preserved in obesity, Le Roux et al. (10) have elevated the prospects that PYY agonists may become effective antiobesity drugs.
They compared the meal-related secretion of PYY in obese (body mass index 
40) and lean (body mass index 22) subjects and showed that for any given caloric load between 250 and 3000 kcal, peak plasma PYY concentration was less in obese than lean subjects. The caloric load required to evoke a given PYY response in the obese subjects was more than double that required in the lean cohort.
The authors showed in the same study that satiety, assessed by visual analog scores (VAS), was also generally lower for a given caloric load in the obese. It was clearly possible, if PYY was equally satiogenic in the obese as in the lean (as these authors have previously reported), that the satiety deficit in the obese could derive from a reduced PYY response.
However, for this to be the case, PYY-induced satiety would need to be a predominant contributor to overall meal-related satiety. The data from Le Roux et al. (10) allow some examination of this proposal. Data extracted from their Fig. 1
, C and D, enable the construction (see Fig. 1) of the satiety (VAS)-PYY concentration response in the context of a meal. On the same graph are plotted data extracted from Fig. 2, A and C, of Le Roux et al. (10), obtained with exogenous infusions of PYY(3–36).
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An implication of this analysis is that the satiety deficit reported by obese individuals does not derive primarily from their PYY deficit. The magnitude of the satiety deficit well exceeded the entire component attributable to PYY. It thus appears more likely that the PYY deficit was a consequence rather than a cause of obesity.
In their discussion, Le Roux et al. (10) reached a similar position via a different route. They induced obesity in mice with high-fat feeding, measured postprandial PYY and saw that it was reduced. PYY mRNA levels in the gut were unaltered with induced obesity, but tissue concentrations in the gut were elevated. Whereas an increase in clearance cannot be precluded, these findings most likely reflect a reduction in stimulated release.
It is unclear, however, whether the reduction in L-cell secretion represents a true impairment of the L-cell’s secretory function, its ability to sense nutrients and other stimuli in the gut lumen, alterations in other modulatory signals (such as from the enteric nervous system or other humoral signals), in the delivery of nutrient to the terminal ileum or in PYY clearance, as examples. Thus far, none of these has been directly investigated.
Finally, the authors (3) have shown that DIO mice parallel obese humans in that they exhibit normal anorectic responses to PYY(3–36). Food intake was reduced by 52 and 39% at 2 and 4 h after 50-µg/kg (12.3 nmol/kg) doses. The effect of PYY to reduce food intake has been controversial, with one multiauthor paper disclaiming such an effect (11). More recent publications, however, affirm the anorectic effect of PYY(3–36) (6, 12, 13, 14, 15, 16, 17, 18, 19).
There is still considerable controversy surrounding the anorectic mechanism of PYY(3–36), with diverging opinion on whether it is mediated via hypothalmic or brainstem structures, whether it involves vagal afferents or the area postrema, and whether it involves Y2 receptors. The extent to which the satiogenic activity of PYY agonists account for weight loss effects is even unclear. For example, gastrointestinal actions, including slowing of gastric emptying (20, 21) and slowing of digestive secretions (22), can also modulate nutrient assimilation.
In summary, Le Roux et al. (10) have advanced the state of the art somewhat with this paper. But their illumination has revealed yet another chasm, namely the basis of L-cell hyposecretion in metabolic disease.
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Footnotes |
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Abbreviations: GLP-1, Glucagon-like peptide-1; PYY, peptide YY; VAS, visual analog scores.
Received September 22, 2005.
Accepted for publication October 7, 2005.
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