Early leptin response to a palatable diet predicts dietary obesity in rats: key role of melanocortin-4 receptors in the ventromedial hypothalamic nucleus.
We have investigated whether interactions between leptin and hypothalamic melanocortin-4 receptors (MC4-Rs) determine individual susceptibility to dietary obesity in rats. Animals with relatively high plasma leptin levels 1 week after presentation of palatable food, before weight increased significantly, subsequently showed lower food intake and weight gain after 8 weeks of palatable feeding than those with low early leptin levels. The rats with lesser weight gain also showed significantly greater down-regulation of MC4-Rs, which mediate hypophagia, in specific hypothalamic areas, namely, the arcuate, dorsomedial, and ventromedial (VMH) nuclei and the median eminence. We suggest that this reflects enhanced receptor exposure to endogenous alpha-melanocyte-stimulating hormone, an appetite-suppressing peptide produced by hypothalamic proopiomelanocortin neurones. It is striking that plasma leptin levels at 1 week were inversely correlated with MC4-R density in the VMH, suggesting that this is a key site of leptin action. The early leptin response to palatable feeding may therefore "program" subsequent feeding behaviour and weight gain by regulating neurones that project selectively to the VMH.
Harrold
J A
JA
Diabetes and Endocrinology Research Group, Department of Medicine, University of Liverpool, England. harrold@liverpool.ac.uk
Williams
G
G
Widdowson
P S
PS
D000818:Animals; D004032:Diet; D015536:Down-Regulation; D004435:Eating; D020738:Leptin / Q000097:blood*; D008297:Male; D009765:Obesity / Q000209:etiology*; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide / Q000378:metabolism*; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism*; D015430:Weight Gain
D020738:Leptin; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide