Effects of leptin on cat intestinal vagal mechanoreceptors

Abstract

Vagal afferent nerve fibres are involved in the transmission to the central nervous system of information relating to food intake and immune reactions. Leptin is involved in the control of food intake and has specific receptors in afferent vagal neurones. To investigate the role of these receptors, we studied the effects of leptin on single vagal afferent activities from intestinal mechanoreceptors in anaesthetized cats. The activity of 35 intestinal vagal mechanoreceptors was recorded by means of glass microelectrodes implanted in the nodose ganglion. Leptin (10 microg), administered into the artery irrigating the upper part of the intestine, induced activation in 17 units (P < 0.001), inhibition in 8 units (P < 0.05), and had no effect on 10 units. The excitatory effects of leptin were blocked by the endogenous interleukine-1beta receptor antagonist, (Il-1ra, 250 microg, I.A.). Cholecystokinin (CCK, 10 microg, I.A.) induced an activatory response only in the two types of units which were responsive to leptin alone. When leptin was administered after CCK, its excitatory effects were enhanced and its inhibitory effects were blocked, whereas it had no effect on the units which were not affected by leptin alone. The interactions between leptin and CCK are specific ones, since other substances (phenylbiguanide, a serotoninergic agonist; substance P) known to activate the mechanoreceptors did not modify the effects of leptin. These results indicate that leptin appears to play a role in the control of immune responses and food intake via intestinal vagal afferent nerve fibres and that there is a functional link between leptin and Il-1beta.

Figure 1. Effects of leptin (10 μg, i.a.) on the activity of type 1 intestinal vagal mechanoreceptor before and after administration of CCK (10 μg, i.a.)

A (control), the basal activity consisted of two bursts of spikes. B, leptin administration (arrow) induced a strong activation of the receptor. C, leptin administration (arrow) 20 min after CCK induced practically continuous discharges of the receptor, indicating that the effects of leptin were enhanced by previous injection of CCK. B, 10 s after A; C, 80 min after B.

Figure 2. Dose-response curve of the effects of leptin (0.1, 1 and 10 μg, i.a.) on the activity of type 1 intestinal vagal mechanoreceptors before and after CCK (10 μg, i.a.)

At each dose the excitatory effects of leptin were enhanced after CCK administration. **P < 0.01 (n = 7).

Figure 3. Statistical analysis of the effects of leptin (Lep), SP, CCK and PBG on the activity of intestinal mechanoreceptors

Leptin, CCK, SP and PBG were intra-arterially administered at a dose of 10 μg. A, type 1 units; B, type 2 units. In A and B, columns C give the mean value of the control responses as 100 %. The effects of various drugs are expressed as mean values compared with the control value. The vertical bars at the top of the columns give the s.e.m.. In type 1 units, all the drugs induced excitatory effects, whereas in type 2 units, only CCK induced excitatory effects. In type 2 units, SP and PBG had no effect, while leptin induced inhibitory effects. *P< 0.05; **P< 0.01; ***P< 0.001; ns: not significant. n (the number of units) is indicated in parentheses above the histograms.

Figure 4. Histograms comparing the effects of arterially administered leptin alone (10 μg), and those of leptin after CCK (10 μg, i.a.) on the activity of a type 1 intestinal vagal mechanoreceptor

A, control; B, leptin administration (arrow); C, leptin administration (arrow) 20 min after CCK. The effects of leptin were enhanced after CCK. Top traces in insets in A, B and C are the same reference waveform as that recorded at the beginning of A. AP s⁻¹: action potential per second.

Figure 5. Statistical analysis of the effects of leptin (Lep, 10 μg, i.a.) on the intestinal vagal mechanoreceptors of types 1 and 2 before and after CCK, SP and PBG

CCK, SP and PBG were intra-arterially administered at a dose of 10 μg. In each group of traces: Aa (n = 10), Ba (n = 5) and Ca(n = 4) showed the effects on type 1 units. Ab(n = 8), Bb (n = 4) and Cb (n = 3) showed the effects on type 2 units. Aa and b, effects of CCK (arrow). Ba and b, effects of SP (arrow). Ca and b, effects of PBG (arrow). For each group of traces, column C gives the mean value of the control response as 100%. Note that the effects of leptin were enhanced after CCK but remained unchanged after SP or PBG. *P< 0.05; **P< 0.01; ns, not significant.

Figure 6. Effects of leptin (10 μg, i.a.) on the activity of a type 1 intestinal mechanoreceptor before and after administration of Il-1ra (250 μg, i.a.)

A (control), the receptor weakly discharged (action potential of large amplitude). B, leptin administration (arrow) strongly activated the receptor. C, 5 min after Il-1ra, administration of leptin (arrow) induced no effect. B, 10 s after A; C, 65 min after B.

Figure 7. Histograms comparing the effects of arterially administered leptin alone (10 μg), with those of leptin after Il-1ra (250 μg, i.a.) on the activity of a type 1 intestinal vagal mechanoreceptor

A, control. B, leptin administration (arrow). C, leptin administration (arrow) 5 min after Il-1ra. The excitatory effect of leptin (B) was blocked by Il-1ra (C). Top traces in insets in A, B and C are the same reference waveform as that recorded at the beginning of A.

Figure 8. Statistical analysis of the effects of leptin (Lep, 10 μg, i.a.) before and after administration of Il-1ra (250 μg, i.a.) on the type 1 intestinal vagal mechanoreceptors

Column C gives the mean value of the control response as 100 %. Note that leptin administered after Il-1ra had no effect. **P < 0.01; ns: not significant (n = 10).