PYY3-36 injection in mice produces an acute anorexigenic effect followed by a delayed orexigenic effect not observed with other anorexigenic gut hormones

Peptide YY (PYY) is secreted postprandially from the endocrine L cells of the gastrointestinal tract. PYY3-36, the major circulating form of the peptide, is thought to reduce food intake in humans and rodents via high-affinity binding to the autoinhibitory neuropeptide Y (NPY) receptor within the arcuate nucleus. We studied the effect of early light-phase injection of PYY3-36 on food intake in mice fasted for 0, 6, 12, 18, 24, and 30 h and show that PYY3-36 produces an acute anorexigenic effect regardless of the duration of fasting. We also show evidence of a delayed orexigenic effect in ad libitum-fed mice injected with PYY3-36 in the early light phase. This delayed orexigenic effect also occurs in mice administered a potent analog of PYY3-36, D-Allo Ile(3) PYY3-36, but not following injection of other anorectic agents (glucagon-like-peptide 1, oxyntomodulin, and lithium chloride). Early light-phase injection of PYY3-36 to ad libitum-fed mice resulted in a trend toward increased levels of hypothalamic NPY and agouti-related peptide mRNA and a decrease in proopiomelanocortin mRNA at the beginning of the dark phase. Furthermore, plasma levels of ghrelin were increased significantly, and there was a trend toward decreased plasma PYY3-36 levels at the beginning of the dark phase. These data indicate that PYY3-36 injection results in an acute anorexigenic effect followed by a delayed orexigenic effect.