Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the agouti obesity syndrome.
Dominant mutations at the agouti locus induce several phenotypic changes in the mouse including yellow pigmentation (phaeomelanization) of the coat and adult-onset obesity. Nonpigmentary phenotypic changes associated with the agouti locus are due to ectopic expression of the agouti-signaling protein (ASP), and the pheomelanizing effects on coat color are due to ASP antagonism of alpha-MSH binding to the melanocyte MC1 receptor. Recently it has been demonstrated that pharmacological antagonism of hypothalamic melanocortin receptors or genetic deletion of the melanocortin 4 receptor (MC4-R) recapitulates aspects of the agouti obesity syndrome, thus establishing that chronic disruption of central melanocortinergic signaling is the cause of agouti-induced obesity. To learn more about potential downstream effectors involved in these melanocortinergic obesity syndromes, we have examined expression of the orexigenic peptides galanin and neuropeptide Y (NPY), as well as the anorexigenic POMC in lethal yellow (A(y)), MC4-R knockout (MC4-RKO), and leptin-deficient (ob/ob) mice. No significant changes in galanin or POMC gene expression were seen in any of the obese models. In situ hybridizations using an antisense NPY probe demonstrated that in obese A(y) mice, arcuate nucleus NPY mRNA levels were equivalent to that of their 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 nucleus, possibly via elevated NPY expression, may have an etiological role in the melanocortinergic obesity syndrome.
Kesterson
R A
RA
Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University Portland, 97201-3098, USA.
Huszar
D
D
Lynch
C A
CA
Simerly
R B
RB
Cone
R D
RD
D054366:Agouti Signaling Protein; D000818:Animals; D019004:Galanin / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D007031:Hypothalamus / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009154:Mutation; D009478:Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics*; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis / Q000235:genetics*; D011506:Proteins / Q000235:genetics*
D054366:Agouti Signaling Protein; D036341:Intercellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D011506:Proteins; D011333:Pro-Opiomelanocortin; D019004:Galanin