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 17 beta -estradiol treatment. The aims of this s tudy 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 hypothala mic neuropeptide Y (NPY). METHODS: Plasma leptin levels, adipose tissue ob gene expression, energy ba lance responses to i.c.v, leptin, hypothalamic Ob-Rb expression and NPY con centration in five separate hypothalamic regions were measured in adult fem ale rats after either ovariectomy or sham operations. RESULTS: Obesity was not associated with hypoleptinemia or decreased ob gen e expression in ovariectomized rats; however, it was associated with insens itivity to central leptin administration. Food intake was less suppressed a nd spontaneous physical activity was less stimulated by leptin. This was no t due to decreased hypothalamic Ob-Rb expression. NPY concentration in the paraventricular nucleus of the hypothalamus was elevated in the ovariectomi zed rats, consistent with leptin insensitivity; however this effect was tra nsient and disappeared as body fat and leptin levels increased further and hyperphagia normalized. CONCLUSION: Impaired central leptin sensitivity and overproduction of NPY m ay contribute to excess fat accumulation caused by estrogen deficiency.