FP08-3 Anorexigenic Estradiol Effects Do Not Involve Leptin-STAT3 Signaling

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP08-Obesity: Novel Mechanisms of Body Weight Regulation
Basic/Translational
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:10 AM
Room 301 (Moscone Center)

Poster Board SAT-709
Joon S Kim*, Janette H Quennell, Mohammed Z Rizwan and Greg M Anderson
University of Otago School of Medical Sciences, Dunedin, New Zealand
The adipose-derived hormone leptin and the sex steroid 17b-estradiol (E2) are critical regulators of body weight. While it is well accepted that leptin acts predominantly via its long-form receptor (LepRb) to induce the phosphorylation of signal transducer and activator of transcription 3 (STAT3), the mechanism underlying E2’s anorexigenic effects are largely unknown. It is thought that the main receptors of these hormones, LepRb and estrogen receptor-alpha (ERα), share an intracellular cross-talk. Consistent with this, E2 is unable to exert its anti-obesity effects in a neural STAT3 knockout mouse model, suggesting that STAT3 plays the critical common pathway via which these two hormones exert their effects (1). A series of experiments were designed to explore the possible interaction between leptin and E2 on STAT3. We first characterized the colocalization of LepRb with ERα in the mouse hypothalamus to determine the extent to which a direct relationship between LepRb-STAT3 and ERα signaling was possible. By crossing LepRb-Cre and Tau-GFP reporter mice, GFP expression was able to be colocalized with ERα immunoreactivity. A relatively low percentage of GFP-positive cells coexpressing ERα were observed in the arcuate nucleus (24.7%), ventromedial hypothalamus (25.7%), caudal dorsomedial hypothalamus (26.0%), and ventral premamillary nucleus (34.8%). However, a higher coexpression was recorded in the preoptic area (88.3%), rostral dorsomedial (63.4%) and lateral hypothalamus (62.3%). To explore the effects of E2 on leptin-induced STAT3 phosphorylation, ovarectomized mice with low, medium, or high levels of chronic E2 replacement received an acute leptin challenge (0.02 mg/kg sc). We observed no increase in the degree of leptin-induced phosphorylated STAT3-positive cell numbers in the arcuate nucleus with higher estrogenic states. Finally, mice with deletion of STAT3 specifically in LepRb-expressing cells were ovarectomised and given either chronic E2 or vehicle implants to test whether E2's weight reducing effects were dependent on LepRb-STAT3 signaling. After 8 days there was no difference in body weight between E2 treatment and controls; data collection still in progress. Here we report quantified analysis of LepRb and ERα colocalization in the murine hypothalamus while also revealing previously undescribed coexpressing populations. Furthermore, we suggest that E2 is likely to exert anorexigenic effects independently of LepRb-STAT3 signaling.

(1) Gao Q, Mezei G, Nie Y, Rao Y, Choi CS, Bechmann I, Leranth C, Toran-Allerand D, Priest CA, Roberts JL 2006 Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nature medicine 13:89-94

Nothing to Disclose: JSK, JHQ, MZR, GMA

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: The Royal Society of New Zealand Marsden Grant; Health Research Council