Differential effects of alpha-, beta- and gamma(2)-melanocyte-stimulating hormones on hypothalamic neuronal activation and feeding in the fasted rat.

Hypothalamic pro-opiomelanocortin neurones have an established role in the control of feeding. While pro-opiomelanocortin is the precursor for at least three melanocortin peptides, alpha-, beta- and gamma-melanocyte-stimulating hormone (MSH), it has been widely assumed that alpha-MSH is the predominant ligand involved. We compared the effects of centrally administered alpha-, beta- and gamma(2)-MSH on hypothalamic neuronal activation and on food intake in rats fasted for 48 h. Significant reductions in food intake were seen with alpha-MSH (first hour) and gamma(2)-MSH (second hour) but not with beta-MSH. The pattern of neuronal activation, assessed by the detection of early growth response factor-1 protein, showed considerable overlap; all three melanocortins activated cells in the arcuate, ventromedial, paraventricular, periventricular and supraoptic nuclei, as well as the preoptic area. alpha-MSH and beta-MSH produced activation in the dorsomedial nuclei while gamma(2)-MSH was only weakly active here. Retrograde labelling by systemic Fluorogold injection revealed that many cells activated by MSH compounds in the arcuate, paraventricular, periventricular and supraoptic nuclei (but not dorsomedial or ventromedial) project outside the blood-brain barrier and are therefore likely to include neuroendocrine cells. Desacetyl-alpha-MSH, which has previously been reported to lack effects on feeding, produced no discernible neuronal activation in the hypothalamus. Our finding that both the pattern of neuronal activation and the distribution of neuroendocrine cells activated in response to these closely related peptides show only partial overlap suggests that, in addition to common pathways, there may exist distinct hypothalamic circuits activated by different pro-opiomelanocortin products. The slower time course of gamma(2)-MSH- versus alpha-MSH-induced suppression of feeding provides further support for the notion that the biological responses to individual melanocortin peptides may involve distinct neuronal mechanisms.