Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y.
OBJECTIVE
Altered fat distribution is a consequence of menopause, but the mechanisms responsible are unknown. Estrogen insufficiency in humans can be modeled using ovariectomized rats. We have shown that increased adiposity in these rats is due to reduced physical activity and transient hyperphagia, and can be reversed with 17beta-estradiol treatment. The aims of this study were to examine whether this altered energy balance is associated with circulating leptin insufficiency, central leptin insensitivity, decreased hypothalamic leptin receptor (Ob-Rb) expression, and/or increased hypothalamic neuropeptide Y (NPY).


METHODS
Plasma leptin levels, adipose tissue ob gene expression, energy balance responses to i.c.v. leptin, hypothalamic Ob-Rb expression and NPY concentration in five separate hypothalamic regions were measured in adult female rats after either ovariectomy or sham operations.


RESULTS
Obesity was not associated with hypoleptinemia or decreased ob gene expression in ovariectomized rats; however, it was associated with insensitivity to central leptin administration. Food intake was less suppressed and spontaneous physical activity was less stimulated by leptin. This was not due to decreased hypothalamic Ob-Rb expression. NPY concentration in the paraventricular nucleus of the hypothalamus was elevated in the ovariectomized rats, consistent with leptin insensitivity; however this effect was transient and disappeared as body fat and leptin levels increased further and hyperphagia normalized.


CONCLUSIONS
Impaired central leptin sensitivity and overproduction of NPY may contribute to excess fat accumulation caused by estrogen deficiency.
Ainslie
D A
DA
Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
Morris
M J
MJ
Wittert
G
G
Turnbull
H
H
Proietto
J
J
Thorburn
A W
AW
D015502:Absorptiometry, Photon; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001823:Body Composition; D001835:Body Weight; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D002149:Energy Intake; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D007031:Hypothalamus / Q000378:metabolism*; D020738:Leptin / Q000235:genetics; D009478:Neuropeptide Y / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D010052:Ovariectomy; D012313:RNA; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002352:Carrier Proteins; D004967:Estrogens; D020738:Leptin; D009478:Neuropeptide Y; C034477:RNA primers; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D012313:RNA