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

• Published in: Diabetes (New York, N.Y.) Vol. 48; no. 2; pp. 267 - 271
• Main Authors: HARROLD, J. A, WIDDOWSON, P. S, WILLIAMS, G
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-02-1999
• Subjects: Animals; Autoradiography; Biological and medical sciences; Diet; Eating - physiology; Energy Metabolism - physiology; Feeding. Feeding behavior; Food Deprivation - physiology; Fundamental and applied biological sciences. Psychology; Hypothalamus - metabolism; Male; Obesity - etiology; Obesity - metabolism; Rats; Rats, Wistar; Rats, Zucker - metabolism; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Corticotropin - metabolism; Receptors, Corticotropin - physiology; Tissue Distribution; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Animal model; Feeding behavior; Rat; Rodentia; Central nervous system; Hypothalamus; Energy balance; Vertebrata; Mammalia; Food intake; Peptidergic receptor; Localization; Brain (vertebrata)
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.48.2.267

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.
J A Harrold ,
P S Widdowson and
G Williams
Department of Medicine, University of Liverpool, UK. [e-mail]
Abstract
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.