Glucagon-like peptide-1 receptor (GLP-1R) agonists such as exendin-4 (Ex-4) affect eating and metabolism and are potential candidates for treating obesity and type II diabetes. In the present study, we tested whether vagal afferents mediate the eating-inhibitory and avoidance-inducing effects of Ex-4. Subdiaphragmatic vagal deafferentation (SDA) blunted the short-term (< 1 h) but not long-term eating-inhibitory effect of i.p.-infused Ex-4 (0.1 μg/kg) in rats. A dose of 1 μg/kg Ex-4 reduced 0.5, 1, 2 and 4 h cumulative food intake in SDA and sham-operated rats to a similar extent. Paradoxically, SDA but not sham rats developed a conditioned flavour avoidance (CFA) after i.p. Ex-4 (0.1 μg/kg). SDA completely blunted the induction of c-Fos expression by Ex-4 in the hypothalamic paraventricular nucleus. Ex-4, however, increased the number of c-Fos expressing cells, independent of intact vagal afferents, in the nucleus accumbens and in the central nucleus of the amygdala, the lateral external parabrachial nucleus, the caudal ventrolateral medulla and the dorsal vagal complex. These data suggest that intact vagal afferents are only necessary for the full expression of the early satiating effect of Ex-4 but not for later eating-inhibitory actions, when circulating Ex-4 might reach the brain via the circulation. Our data also dissociate the satiating and avoidance-inducing effects of the low Ex-4 dose tested under our conditions and suggest that vagal afferent signalling may protect against the development of CFA. Taken together, these findings reveal a complex role of vagal afferents in mediating the effects of GLP-1R activation on ingestive behaviour.

Peptide tyrosine-tyrosine (PYY) is implicated in eating control, but the site(s) and mechanism(s) of its action remain uncertain. We tested acute effects of intrameal hepatic portal vein (HPV) PYY(3-36) infusions on eating in adult, male rats and measured HPV and jugular vein (JV) plasma levels of PYY in response to a solid, mixed-nutrient meal. We also examined the effects of HPV PYY(3-36) infusions on JV plasma levels, flavor acceptance, and neuronal activation. Intrameal HPV PYY(3-36) infusions [1 and 3 nmol/kg body weight (BW)] selectively reduced (P < 0.05) ongoing meal size. HPV PYY levels increased (P < 0.05) during a chow (12.5 kcal) or an isocaloric high-fat meal. JV PYY levels were generally lower than HPV levels but also increased in response to the chow meal. HPV PYY(3-36) infusion (1 nmol/kg BW) caused a greater increase in JV PYY than a meal, but neither 1 nor 3 nmol/kg BW PYY(3-36) caused conditioned flavor avoidance. HPV PYY(3-36) (1 nmol/kg BW) increased the number of c-Fos-expressing cells in the nucleus tractus solitarii, the hypothalamic arcuate and paraventricular nuclei, the central area of the amygdala, and the nucleus accumbens but not in the area postrema and parabrachial nucleus. These data show that HPV infusions of PYY(3-36) inhibit eating in rats without causing avoidance, and they identify some brain areas that might be involved. Endogenous PYY may induce satiation by acting directly in the brain, but further studies should examine whether PYY(3-36) administrations that mimic the meal-induced increase in plasma PYY are sufficient to inhibit eating.

No abstract

The gastrointestinal hormone peptide tyrosine tyrosine 3-36 (PYY(3-36)) has attained broad recognition with respect to its involvement in energy homeostasis and the control of food intake. It is mainly secreted by distal intestinal enteroendocrine L-cells in response to eating and exerts neurally mediated, paracrine and endocrine effects on various target organs. In addition to its gastrointestinal effects, PYY(3-36) has long been known to inhibit food intake. Recent closer examination of the effects of PYY(3-36) revealed that this gut-derived peptide also influences a wide spectrum of behavioral and cognitive functions that are pivotal for basic processes of perception and judgment, including central information processing, salience learning, working memory, and behavioral responding to novelty. Here, we review the effects of PYY(3-36) that go beyond food intake and provide a conceptual framework suggesting that several apparently unrelated behavioral actions of PYY(3-36) may actually reflect different manifestations of modulating the central dopamine system.

The gastrointestinal hormone PYY(3-36) is a preferential Y2 neuropeptide Y (NPY) receptor agonist. Recent evidence indicates that PYY(3-36) acts on central dopaminergic pathways, but its influence on dopamine-dependent behaviours remains largely unknown. We therefore explored the effects of peripheral PYY(3-36) treatment on the behavioural responses to novelty and to dopamine-activating drugs in mice. In addition, we examined whether PYY(3-36) administration may activate distinct dopamine and γ-aminobutyric acid (GABA) cell populations in the mesoaccumbal and nigrostriatal pathways. We found that i.p. PYY(3-36) injection led to a dose-dependent increase in novel object exploration. The effective dose of PYY(3-36) (1 μg/100 g body weight) also potentiated the locomotor reaction to the indirect dopamine receptor agonist amphetamine and increased stereotyped climbing/leaning responses following administration of the direct dopamine receptor agonist apomorphine. PYY(3-36) administration did not affect activity of midbrain dopaminergic cells as evaluated by double immuno-enzyme staining of the neuronal early gene product c-Fos with tyrosine hydroxylase. PYY(3-36) did, however, lead to a marked increase in the number of cells co-expressing c-Fos with glutamic acid decarboxylase in the nucleus accumbens and caudate putamen, indicating activation of GABAergic cells in dorsal and ventral striatal areas. Our results support the hypothesis that acute administration of the preferential Y2 receptor agonist PYY(3-36) modulates dopamine-dependent behaviours. These effects do not seem to involve direct activation of midbrain dopamine cells but instead are associated with neuronal activation in the major input areas of the mesoaccumbal and nigrostriatal pathways.