Altered energy balance causes selective changes in melanocortin-4 (MC4-R),but not melanocortin-3 (MC3-R), receptors in specific hypothalamic regions- Further evidence that activation of MC4-R is a physiological inhibitor of feeding

We have examined the effects of underfeeding and obesity ore the density of hypothalamic melanocortin MC3 and MC4 receptors (MC3-R and MC4-R, respecti vely), which may mediate the hypophagic effects of alpha-melanocyte-stimula ting hormone (MSH) in the rat. MC3-R and MC4-R were measured by quantitativ e autoradiography in brain sections using I-125-labeled Nle(4)-D-Phe(7)-alp ha-MSH (I-125-NDP-MSH) and discriminated by masking MC3-R with excess unlab elled gamma(2)-MSH. High densities of MC4-R occurred in the ventromedial (V MH) and arcuate (ARC) nuclei, median eminence (ME), and medial habenular nu cleus (MHb), with lower densities in the dorsomedial hypothalamus (DMH) and forebrain regions. MC3-R were confined to the VMH, ARC, and MHb. After 10- days of food restriction (14% weight loss), density of MC4-R was significan tly increased by 20-65% in the VMH, ARC, ME, and DMH, with no changes elsew here. Similarly, obese (fa/fa) Zucker rats showed 43-98% increases in MC4-R in the same regions. By contrast, rats with diet-induced obesity (18% heav ier than controls) showed significantly decreased binding to MC4-R, especia lly in the VMH, ARC, and ME. MC3-R showed no significant alterations in any model. We suggest that increased density of MM4-R with food restriction an d in obese Zucker rats reflects receptor upregulation secondary to decrease d release of a-MSH, consistent with increased hunger in these models. Conve rsely, downregulation of MC4-R in diet-induced obesity may indicate increas ed alpha-MSH secretion in an attempt to limit overeating. This alpha-MSH/MC 4-R system may be inhibited by leptin and/or insulin. MC3-R are not apparen tly involved in regulating feeding.