Agonists for neuropeptide Y receptors Y1 and Y5 stimulate different phases of feeding in guinea pigs

Abstract

1. The stimulatory effect of neuropeptide Y (NPY) on food intake is well established but the roles of the receptor subtypes Y(1) and Y(5) have been difficult to define. We have studied the effects of two novel Y(1)-preferring and two Y(5)-preferring agonists on feeding in guinea pigs. 2. The Y(1)-preferring receptor agonists [Arg(6),Pro(34)]pNPY and [Phe(7),Pro(34)]pNPY had high affinity for the Y(1) receptor (K(i) values 0.07 and 0.04 nM, respectively) and nanomolar affinity for the Y(5) receptor. Administration of either compound into the third brain ventricle increased food intake equally to NPY. 3. The Y(5) agonist [Ala(31),Aib(32)]pNPY displayed a moderate affinity for the Y(5) receptor (K(i) 7.42 nM) and a low affinity for Y(1) (K(i) 1.7 micro M). This compound had only a modest effect on feeding. 4. The other Y(5)-preferring peptide [cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]hPP had a higher affinity at the Y(5) receptor (K(i) 1.32 nM) and also at the Y(1) receptor (K(i) 85 nM). It potently stimulated feeding: the food consumption after administration of this peptide was two-fold compared to NPY. 5. Our results support the view that both the receptor subtypes Y(1) and Y(5) are involved in the stimulation of feeding. As the action profiles of the Y(1) and Y(5) agonists on feeding parameters were different, it seems that they influence different phases of eating.

Figure 1

Competition of ¹²⁵I-pPYY binding by Y₁ and Y₅ agonists to membranes expressing the guinea pig Y₁, Y₂ and Y₅ receptors. Results shown are from one typical experiment performed in duplicate. Nonspecific binding was defined in the presence of 100 nM pNPY. K_i values are listed in Table 1.

Figure 2

Cumulative food intake induced by 3.6 nmol of NPY, [Arg⁶,Pro³⁴]pNPY, [Phe⁷,Pro³⁴]pNPY, [Ala³¹,Aib³²]pNPY or [cPP^1–7,NPY^19–23,Ala³¹,Aib³²,Gln³⁴]hPP following i.c.v. administration to conscious guinea pigs. Mean±s.e.m., n=8–10 in each group. Points marked with * are statistically different from the controls: ^*P<0.05; ^**P<0.01.

Figure 3

Food intake (upper panel), eating time (middle panel) and number of meals (lower panel) after i.c.v. administration of NPY, the Y₁-preferring [Arg⁶,Pro³⁴]pNPY or [Phe⁷,Pro³⁴]pNPY and the Y₅-preferring [Ala³¹,Aib³²]pNPY or [cPP^1–7,NPY^19–23,Ala³¹, Aib³²,Gln³⁴]hPP to conscious guinea pigs. Mean±s.e.m., n=8–10 in each group. Columns marked with * are statistically different from the controls: *P<0.05; ^**P<0.01; ^***P<0.001 and those marked with # differ (P<0.05) significantly from the group treated with 3.6 nmol [cPP^1–7,NPY^19–23,Ala³¹,Aib³²,Gln³⁴]hPP.

Figure 4

Latency to eat (upper panel), average meal size (middle panel) and meal duration (lower panel) after i.c.v. administration of NPY, the Y₁-preferring [Arg⁶,Pro³⁴]pNPY or [Phe⁷,Pro³⁴]pNPY and the Y₅-preferring [Ala³¹,Aib³²]pNPY or [cPP^1–7,NPY^19–23,Ala³¹, Aib³²,Gln³⁴]hPP to conscious guinea pigs. Mean±s.e.m., n=8–10 in each group. Columns marked with # differ (P<0.05) from the group treated with 3.6 nmol [cPP^1–7,NPY^19–23,Ala³¹, Aib³²,Gln³⁴]hPP.