The effects of chemical vagotomy of leptin-induced inhibition of food intake J.D. Patel & I.S. Ebenezer. Neuropharmacology Research Group, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2DT, U.K.

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We have recently reported that i.p., but not s.c., administration of leptin produces a short lasting decrease in food intake in hungry rats and suggested that leptin released from the stomach during a meal may play a role as a short-term peripheral satiety factor (Patel et al., 2001, 2002). The study was undertaken to investigate whether i.p. administered leptin activates vagal afferents to signal the brain to inhibit food intake.

Chemical vagotomy was carried out using a slightly modified method described previously (Brzozowski et al., 1996). Male Wistar rats (n=6; b. wt. 320 -340 g) were pretreated with atropine sulphate (1 mg kg^-1, s.c.) and were anaesthetised with Equithesin daily on 3 consecutive days. Following induction of anaesthesia, the animals were slowly infused i.p. with the following doses of capsaicin: 25 mg kg^-1 (day 1), 50 mg kg^-1 (day 2) and 50 mg kg^-1 (day 3). Control rats (n=6) underwent the same experimental procedure, but were injected with vehicle, instead of capsaicin. The success of the c-fibre lesion of the afferent vagus was confirmed by (a) the absence of abdominal constrictions to i.p. administration of 0.01% acetic acid, and (b) the attenuation of the hypophagic effect of i.p. administration of cholecystokinin (2 and 4 µg kg^-1). Although it is possible that capsaicin treatment also affected other sensory nerves besides vagal afferents, we tried to minimise such collateral damage by administering the capsaicin by the i.p., rather than the s.c. route, so that the main effects would be on the gastric vagal afferents. Two weeks later, the rats in both groups were fasted for 21h and injected i.p. with either vehicle or leptin (25 µg kg^-1) immediately prior to being placed singly in experimental cages. The amount of food consumed by each animal was measured at 15, 30 and 60 min. A cross-over design was used with each rats receiving both treatments; 3 days separated successive trials.

The results are shown in the Fig. 1. Control rats displayed a reduction in cumulative food intake during the first 15 and 30 min after i.p. administration of leptin compared with vehicle treatment. By contrast, rats that had been treated with capsaicin did not display a reduction in food intake after i..p. administration of leptin. The results indicate that chemical vagotomy with capsaicin abolishes the inhibitory action of leptin (25 µg kg^-1 i.p) on food intake and suggests that the hypophagic effect is dependent on intact vagal afferent nerves. The recent demonstration that leptin receptors are present on vagal afferents (Buyse et al., 2001) lend further credence to the hypothesis that leptin released from the stomach during a meal stimulates vagal afferents to signal the brain to produce satiety.

Fig 1. The effects of i.p. administration of leptin (25 mg kg-1) on food intake in (A) chemically vagotomised rats (n=6) and (B) control (sham-treated) rats that were fasted for 21h. Saline Leptin. Vertical lines represent + s.e.mean **P<0.01, *P<0.01 (paired t-test).

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