Effects of PYY3-36 and GLP-1 on energy intake, energy expenditure, and appetite in overweight men

term administration of peptide YY (PYY)3–36 and glucagonlike peptide-1 (GLP-1) separately leads to a reduction in energy intake by mechanisms involving changes in central regulation of appetite (12). Delays in gastric emptying rates have also been proposed to play a role, but this is controversial (12, 41). As GLP-1 and PYY are cosecreted from intestinal L-cells upon feeding, there is great interest in investigating the satiating effect of these hormones in combination, with the goal being to more effectively mimic the physiology of the fed state. In the two human studies where the effects of coinfusion of PYY3–36 and GLP-1 were investigated, additive inhibitory effects on energy intake were reported compared with being given separately (13, 28). These findings were supported by reports of increased sensations of fullness and reduction in hunger following the combined administration of PYY3–36 and GLP-1 but not after single administrations (13). In mice, coadministration of Ex-4, a long-acting GLP-1 analog, and PYY3–36 decreased energy intake in a synergistic manner (i.e., an effect that was greater than the sum of their individual effects) (40), but synergistic effects have not been demonstrated in human studies. In addition, both PYY and GLP-1 have been suggested to affect hedonic regulation of energy intake (27), and an additive effect of GLP-1 and PYY3–36 on activity in brain regions associated with reward-based eating has been reported (13). The mechanisms behind potential synergistic effects are unknown, but nausea has been suspected to be involved, since nausea is a common side effect of supraphysiological plasma levels of both GLP-1 and PYY3–36 (15, 38). However, the role of nausea in studies reporting a decrease in energy intake and appetite is not clear. If the anorexigenic effect of GLP-1 and PYY3–36 is potentiated by coadministration, this may allow the use of lower doses, thereby avoiding excess nausea without simultaneously attenuating the wanted inhibitory effect on food intake.