A Novel, Centrally Acting Mammalian Aminosterol, ENT-03, Induces Weight Loss in Obese and Lean Rodents.

Denise Barbut,William A. Kinney,Hsiao-Huei Chen,Alexandre F. R. Stewart,Jacob Hecksher-Sorensen, Chen Zhang,Alexander Fleming, Michael Zemel,Michael Zasloff

Diabetes, Obesity and Metabolism（2024）

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Abstract

ENT-03, a spermine bile acid we recently discovered in the brain of newborn mice acts centrally to regulate energy and metabolism. Obese, diabetic (ob/ob) mice treated with five doses of ENT-03 over 2 weeks, demonstrated a rapid decrease in blood glucose levels into the range seen in non-obese animals, prior to any significant weight loss. Weight fell substantially thereafter as food intake decreased, and serum biochemical parameters normalized compared with both vehicle and pair-fed controls. To determine whether ENT-03 could be acting centrally, we injected a single dose of ENT-03 intracerebroventricularly to Sprague-Dawley rats. Weight fell significantly and remained below vehicle injected controls for an extended period. By autoradiography, ENT-03 localized to the arcuate nucleus of the hypothalamus, the choroid plexus and cerebrospinal fluid. Significant cFos activation occurred in multiple anatomical regions within the hypothalamus and brainstem involved in appetite suppression, food-entrained circadian rhythmicity, autonomic function, and growth. These data support a role for ENT-03 in the treatment of type 2 diabetes and obesity. Phase 1 studies in subjects with obesity and diabetes are currently in progress.

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Key words

aminosterol,obesity,PTP1B inhibitor,trodusquemine,type 2 diabetes

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【要点】：研究发现了新型中枢作用的哺乳动物氨基甾醇ENT-03，能有效诱导肥胖和非肥胖鼠类体重下降，并改善血糖水平。

【方法】：通过给予ENT-03口服剂量，观察其在肥胖和非肥胖鼠类中的体重、血糖水平以及生化参数的变化，并通过中枢注射验证其作用机制。

【实验】：对肥胖的db/db小鼠进行ENT-03治疗，共五次剂量，持续两周，观察到血糖水平快速下降至正常范围，随后体重显著下降，同时使用Sprague-Dawley大鼠进行脑室注射ENT-03，结果体重显著下降并持续低于对照组。ENT-03在弧形核、脉络丛和脑脊液中定位，并在多个与食欲抑制相关的下丘脑和脑干区域引发cFos激活。实验使用的数据集包括db/db小鼠和Sprague-Dawley大鼠的生理参数。