Neuropeptide Y and Agouti Related Protein

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Neuropeptide Y (NPY) is a 36 amino acid neu-ropeptide expressed in the CNS and, in particular, in the ARC, representing one of the most potent orexigenic factors studied so far [3].

The intracerebroventricular administration of NPY stimulates food intake in rodents after acute injection [2], while chronic treatment induces hyperphagia and weight gain, coupled with decrease in energy expenditure [2, 4]. Interestingly, NPY administration also inhibits luteinising hormone (LH) secretion [5], underlining the tight relationship between energy balance, fat mass and the activity of the reproductive system. Among the physiological regulators, fasting has been shown to be an important stimulator of NPY expression in animals. In fact, maximal NPY concentration in PVN is observed before and during feeding, suggesting a possible role in meal initiation [2].

Notably, despite the clear orexigenic effects of NPY administration, NPY knockout mice have normal body weight and show weight variation similar to control animals in both overfeeding and fasting conditions [2,6, 7],likely as a consequence of the activation of other orexigenic pathways aimed to preserve the feeling of hunger.

NPY exerts its actions via five specific receptor subtypes, of which the Y5 receptor has been described as the most important for the activity of the peptide [2,8].

Neurons secreting NPY also co-express agouti-related protein (AgRP) [9], a 132 amino acid protein endowed with remarkable NPY-independent orexigenic actions [2, 10]. Specifically, AgRP increases food intake, acting as an endogenous antagonist of melanocortin (MC) 3 and MC4 receptors, thus inhibiting the anorectic action of a-melanocyte-stimulating hormone (MSH) [2,7].

The acute intracerebroventricular administration of AgRP in rodents increases food intake for up to 6 days [2] and chronic treatment determines an important weight gain [11].

NPY/AgRP neurons represent the most important target of central and peripheral orexigenic and anorectic signals. In particular, they are inhibited by leptin and insulin and activated by the orexigenic peptide ghrelin [12-14]. Interestingly, an intestinal peptide, named PYY, the chemical structure of which closely resembles that of NPY [2,10,15], has been reported to exert its anorectic effect acting as an antagonist of the NPY Y2 receptor. In fact, its administration is devoid of any effect in Y2 knockout mice [15].

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