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 on the density of hypothalamic melanocortin MC3 and MC4 receptors (MC3-R and MC4-R, respectively), which may mediate the hypophagic effects of alpha-melanocyte-stimulating hormone (MSH) in the rat. MC3-R and MC4-R were measured by quantitative autoradiography in brain sections using 125I-labeled Nle4-D-Phe7-alpha-MSH (125I-NDP-MSH) and discriminated by masking MC3-R with excess unlabelled gamma2-MSH. High densities of MC4-R occurred in the ventromedial (VMH) and arcuate (ARC) nuclei, median eminence (ME), and medial habenular nucleus (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 significantly increased by 20-65% in the VMH, ARC, ME, and DMH, with no changes elsewhere. 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% heavier than controls) showed significantly decreased binding to MC4-R, especially in the VMH, ARC, and ME. MC3-R showed no significant alterations in any model. We suggest that increased density of MC4-R with food restriction and in obese Zucker rats reflects receptor upregulation secondary to decreased release of alpha-MSH, consistent with increased hunger in these models. Conversely, downregulation of MC4-R in diet-induced obesity may indicate increased alpha-MSH secretion in an attempt to limit overeating. This alpha-MSH/MC4-R system may be inhibited by leptin and/or insulin. MC3-R are not apparently involved in regulating feeding.
Harrold
J A
JA
Department of Medicine, University of Liverpool, UK. harrold@liverpool.ac.uk
Widdowson
P S
PS
Williams
G
G
D000818:Animals; D001345:Autoradiography; D004032:Diet; D004435:Eating / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D005508:Food Deprivation / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000378:metabolism* / Q000502:physiology; D014018:Tissue Distribution
D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin