The pharmacological targeting of polyamine metabolism is currently under the spotlight for its potential in the prevention and treatment of several age-associated disorders. Here, we report the finding that triethylenetetramine dihydrochloride (TETA), a copper-chelator agent that can be safely administered to patients for the long-term treatment of Wilson disease, exerts therapeutic benefits in animals challenged with hypercaloric dietary regimens. TETA reduced obesity induced by high-fat diet, excessive sucrose intake, or leptin deficiency, as it reduced glucose intolerance and hepatosteatosis, but induced autophagy. Mechanistically, these effects did not involve the depletion of copper from plasma or internal organs. Rather, the TETA effects relied on the activation of an energy-consuming polyamine catabolism, secondary to the stabilization of spermidine/spermine N1-acetyltransferase-1 (SAT1) by TETA, resulting in enhanced enzymatic activity of SAT. All the positive effects of TETA on high-fat diet-induced metabolic syndrome were lost in SAT1-deficient mice. Altogether, these results suggest novel health-promoting effects of TETA that might be taken advantage of for the prevention or treatment of obesity.

中文翻译：

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SAT1 的化学激活可纠正饮食引起的代谢综合征。

多胺代谢的药理学靶向目前因其在预防和治疗几种与年龄相关的疾病方面的潜力而受到关注。在这里，我们报告了三亚乙基四胺二盐酸盐 (TETA) 的发现，这是一种铜螯合剂，可以安全地用于长期治疗威尔森氏病的患者，在高热量饮食方案挑战的动物中发挥治疗作用。TETA 减少了由高脂肪饮食、过量蔗糖摄入或瘦素缺乏引起的肥胖，因为它减少了葡萄糖耐受不良和肝脂肪变性，但诱导了自噬。从机制上讲，这些影响不涉及血浆或内脏器官中铜的消耗。相反，TETA 效应依赖于耗能多胺分解代谢的激活，继发于 TETA 稳定亚精胺/精胺 N1-乙酰转移酶-1 (SAT1)，导致 SAT 的酶活性增强。在 SAT1 缺陷小鼠中，TETA 对高脂饮食诱导的代谢综合征的所有积极作用都消失了。总之，这些结果表明 TETA 具有新的健康促进作用，可用于预防或治疗肥胖症。