Suppression of Weight Gain in Ovarectomized High-Fat Diet Rats and in Female Monkeys By Treatment with ESN364 (NK3 Antagonist)
Presentation Number: OR19-6
Date of Presentation: April 4th, 2017
Sophie Noel, Catherine Sorlet, Sandrine Hospied, Clement Mompied, Anne-France Hartiel, Letizia Aloisantoni, Hamid R Hoveyda and Graeme L Fraser*
Abdominal adiposity is a common symptom of menopause. Estrogen withdrawal has profound effects on weight gain in rat models especially when combined with the metabolic insult of high-fat diet (HFD). Hypothalamic KNDy neuron signaling is implicated in female weight gain caused by gonadotropic and/or metabolic obesogenic insults1,2. Neurokinin B (NKB) is a key modulator of KNDy neuron activity via its activation of the NK3 receptor (NK3R). The aim of the current study was to investigate whether the NK3R antagonist, ESN364, affects weight gain in females. In the first experiment, female Sprague-Dawley rats (5-months old, ~350g) were subjected to bilateral ovariectomy (OVX) or sham surgery (SHAM). All rats were then placed on HFD for 21 days whereafter oral dosing of ESN364 (30 mg/kg, BID) was initiated (versus vehicle control, VEH) for a period of 12 days (HFD maintained). Body weight increases over the first 21-day period on HFD were 9.4% for SHAM rats and 26.7% for OVX rats. ESN364 treatment decreased body weight in OVX rats (p<0.01, vs VEH) but had no effect on SHAM rats. The weight reduction corresponded to an acute rise in serum leptin levels over the first four days of ESN364 treatment in OVX rats (p<0.01 vs VEH) whereas no change in leptin was observed in SHAM. The expected rise in plasma LH levels was observed in OVX vs SHAM rats (p<0.0001), and ESN364 treatment decreased LH levels in OVX rats (p<0.001 vs. VEH). Quantitative RT-PCR analysis on hypothalamic tissues collected 3 hours after final dosing from both OVX and SHAM rats revealed that ESN364 treatment decreased expression of receptors (eg. Tacr3 (NK3R), Esr1 (ERa), Oprk1 (KOR), LepR) implicated in KNDy signaling. In the second experiment, sexually-mature female cynomolgus monkeys (4y old, 2.7-3.8 kg, N=6/grp) on normal, lab diet were dosed orally for 90 days with ESN364 (50 mg/kg QD) versus vehicle control. ESN364-treated monkeys had a 1% increase in body weight over the course of treatment compared to a 12% increase for VEH ; differences in body weight gain were not associated with any changes in food intake nor general health of the animals. DEXA scans revealed that ESN364 treatment prevented an increase in %fat/total mass (p<0.05 vs VEH) ; ESN364 did not affect bone or lean mass. Corresponding serum leptin levels were acutely and significantly increased 48h after initial ESN364 dosing relative to vehicle controls (p<0.05). These data provide additional evidence for the importance of KNDy signaling in response to both metabolic and gonadotropic obesogenic insults in females and further demonstrate that such weight gain may be reversed by treatment with an NK3 antagonist.
Disclosure: SN: Employee, OGEDA. CS: Employee, OGEDA. SH: Employee, OGEDA. CM: Employee, OGEDA. AFH: Employee, OGEDA. LA: Employee, OGEDA. HRH: Researcher, OGEDA. GLF: Chief Scientific Officer, OGEDA.