Ra. Kesterson et al., INDUCTION OF NEUROPEPTIDE-Y GENE-EXPRESSION IN THE DORSAL MEDIAL HYPOTHALAMIC NUCLEUS IN 2 MODELS OF THE AGOUTI OBESITY SYNDROME, Molecular endocrinology, 11(5), 1997, pp. 630-637
Dominant mutations at the agouti locus induce several phenotypic chang
es in the mouse including yellow pigmentation (phaeomelanization) of t
he coat and adult-onset obesity. Nonpigmentary phenotypic changes asso
ciated with the agouti locus are due to ectopic expression of the agou
ti-signaling protein (ASP), and the pheomelanizing effects on coat col
or are due to ASP antagonism of alpha-MSH binding to the melanocyte MC
1 receptor. Recently it has been demonstrated that pharmacological ant
agonism of hypothalamic melanocortin receptors or genetic deletion of
the melanocortin 4 receptor (MC4-R) recapitulates aspects of the agout
i obesity syndrome, thus establishing that chronic disruption of centr
al melanocortinergic signaling is the cause of agouti-induced obesity.
To learn more about potential downstream effecters involved in these
melanocortinergic obesity syndromes, we have examined expression of th
e orexigenic peptides galanin and neuropeptide Y (NPY), as well as the
anorexigenic POMC in lethal yellow (AY), MC4-R knockout (MC4-RKO), an
d leptin-deficient (ob/ob) mice. No significant changes in galanin or
POMC gene expression were seen in any of the obese models. In situ hyb
ridizations using an antisense NPY probe demonstrated that in obese AY
mice, arcuate nucleus NPY mRNA levels were equivalent to that of thei
r C57BL/6J littermates. However, NPY was expressed at high levels in a
new site, the dorsal medial hypothalamic nucleus (DMH). Expression of
NPY in the DMH was also seen in obese MC4-RKO homozygous (-/-) mice,
but not in lean heterozygous (+) or wild type (+/+) control mice. This
identifies the DMH as a brain region that is functionally altered by
the disruption of melanocortinergic signaling and suggests that this n
ucleus, possibly via elevated NPY expression, may have an etiological
role in the melanocortinergic obesity syndrome.