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Food deprivation decreases responsiveness of ventromedial hypothalamic neurons to melanocortins

The melanocortin system is involved in regulation of food intake and energy balance. Melanocyte‐stimulating hormone (α‐MSH) is an endogenous melanocortin receptor (MC‐R) agonist. It acts on MC3/4 receptors to reduce appetite and to increase energy expenditure. The production of α‐MSH is reduced during food deprivation, but MC4‐R density is increased. The net effect of reduced α‐MSH production and increased receptor level is not clear. To address this question, responses of ventromedial hypothalamic (VMH) neurons to melanotan II (MTII; a synthetic analogue of α‐MSH) were recorded in brain slices from fed and food‐deprived rats. Responses to the highest dose MTII were observed in 61% of VMH neurons from fed rats but only 33% of VMH neurons from food‐deprived rats. To assess a possible mechanism by which responsiveness to melanocortins is diminished even though receptor number is augmented during fasting, we examined the effect of agouti gene‐related peptide (AGRP), an endogenous MC‐R antagonist that stimulates food intake. The synthesis of AGRP increases during fasting. AGRP significantly reduced VMH responsiveness to MTII. Additionally, AGRP by itself evoked neuronal responses, in contrast to synthetic MC‐R antagonists. AGRP (1 nM) induced a predominant inhibitory effect on VMH neurons in food‐deprived rats but not in fed rats. In the presence of AGRP, MTII induced a significant inhibition of neuronal activity in deprived rats, but not in fed rats. Inhibition of VMH neurons reduces energy expenditure and the satiety signal. These findings suggest that although food deprivation increases MC4‐R density, it nevertheless reduces the effectiveness of melanocortins on VMH neurons, possibly by the involvement of AGRP. © 2004 Wiley‐Liss, Inc.