Effects of Estradiol on Cerebrospinal Fluid Levels of Agouti-Related Protein in Ovariectomized Rhesus Monkeys

Abstract

Hypothalamic proopiomelanocortin (POMC)-derived MSH peptides and the melanocortin receptor antagonist, agouti-related protein (AgRP), interact to regulate energy balance. Both POMC and AgRP neurons express estrogen receptors, but little is known about estrogen regulation of the melanocortin system in the primate. We have therefore examined the effects of physiological doses of estradiol (E2) on POMC and AgRP in lumbar cerebrospinal fluid (CSF) of ovariectomized monkeys. POMC prohormone was measured by ELISA. AgRP was measured by RIA (sensitive for the more biologically active C-terminal AgRP(83-132) but also detects full-length AgRP) and by ELISA (measures primarily full length AgRP). In the first experiment, 14 animals were studied before and after 3 wk of E2. CSF POMC did not change, but AgRP(RIA) decreased from 7.9 +/- 1.2 to 4.7 +/- 1.2 fmol/ml after E2 (P = 0.03) and the POMC/AgRP(RIA) ratio increased from 4.2 +/- 0.89 to 6.8 +/- 1.04 (P = 0.04). AgRP(ELISA) did not change, but the ratio of AgRP(RIA) compared with AgRP(ELISA) was reduced after E2 (P = 0.02). In the second experiment, 11 animals were studied after 6 wk of E2, and similar changes were noted. The degree of AgRP(RIA) suppression with E2 was inversely related to body mass index (r = 0.569; P = 0.03). These results show for the first time that E2 suppresses AgRP(C-terminal) in CSF, increases the POMC to AgRP ratio, and may decrease AgRP processing, thus leading to increased melanocortin signaling. Furthermore, obesity was associated with resistance to the suppressive effects of E2 on AgRP, analogous to what is seen with obesity and leptin resistance.

Proopiomelanocortin, agouti-related protein, and leptin in human cerebrospinal fluid: correlations with body weight and adiposity

“…CSF POMC was higher in males than in females, but the negative correlation between CSF POMC and leptin and BMI remained when the sexes were analyzed separately. This is similar to our study in female monkeys that showed negative correlations between CSF POMC and leptin and BMI (39). These results suggest that POMC plays a primary role in regulating body weight and adiposity.…”

“…AgRP immunoactivity was characterized in a 10-ml CSF pool from a male subject that was concentrated using an Amicon Ultra Centrifugal Filter (Millipore) and subjected to reverse phase HPLC. Samples were eluted with a gradient of 80% acetronitrile containing 0.1% TFA (39). Statistical analysis.…”

Genomics of estradiol-3-sulfate action in the ovine fetal hypothalamus

“…During proestrus, E 2 stimulates NPY expression and release, which in turn contribute to the stimulation of preovulatory GnRH secretion into the hypophysial portal vessels (17). Despite this stimulatory action in these pathways, chronic administration of E 2 has predominately anorectic properties (6,48) in rats and monkeys that depend on the inhibition of NPY and AGRP expression and release (6,14). In contrast to the present results with E 2 S, several reports have demonstrated inhibition of NPY by E 2 .…”

“…E 2 treatment of ovariectomized rats decreased both NPY and AGRP mRNA in the arcuate nucleus (36). Similarly, in rhesus monkeys E 2 decreased AGRP and increased POMC secretion into cerebrospinal fluid (48). The upregulation of NPY and AGRP by E 2 S in the present study could be the consequence of an unknown stimulatory action of E 2 in subpopulations of NPY-AGRP neurons or of non-ER-mediated E 2 S action, although differences of E 2 action between fetal and adult life and of between species cannot be discounted.…”

Sex differences in the physiology of eating

“…The authors also investigated the effects of estradiol treatment, but these data are difficult to interpret physiologically because of the high doses used (2 g centrally and 150 g peripherally, please see Hormone treatment regimens). Whether AgRP/NPY neurons are involved in the periovulatory decrease in eating in other species has not been tested, although ovariectomy increased hypothalamic NPY and AgRP mRNA contents in rats (130) and estradiol reduced the concentration of AgRP in the cerebrospinal fluid of ovariectomized rhesus monkeys (810). Central injections of AgRP had similar effects in estradiol-treated and control ovariectomized rats (562,633), which, together with Olofsson et al's (527) data, suggests that estrogens may modulate AgRP synthesis and release rather than MC 4 receptor function or downstream mechanisms.…”