Obesity is a global epidemic that drives morbidity and mortality through cardiovascular disease, diabetes, and non-alcoholic fatty liver disease (NAFLD). No definitive therapy has been approved to improve glycemic control and treat NAFLD in obese patients. Here, we investigated a semi-synthetic, long chain, structurally-engineered fatty acid-1024 (SEFA-1024), as a treatment for obesity-induced hyperglycemia, insulin-resistance, and fatty liver disease in rodent models. A single dose of SEFA-1024 was administered to evaluate glucose tolerance and active glucagon-like peptide 1 (GLP-1) in lean rats in the presence and absence of a DPP-4 inhibitor. The effects of SEFA-1024 on weight loss and glycemic control were assessed in genetic (ob/ob) and environmental (high-fat diet) murine models of obesity. Liver histology, serum liver enzymes, liver lipidomics, and hepatic gene expression were also assessed in the high-fat diet murine model. SEFA-1024 reversed obesity-associated insulin resistance and improved glycemic control. SEFA-1024 increased active GLP-1. In a long-term model of diet-induced obesity, SEFA-1024 reversed excessive weight gain, hepatic steatosis, elevated liver enzymes, hepatic lipotoxicity, and promoted fatty acid metabolism. SEFA-1024 is an enterohepatic-targeted, eicosapentaenoic acid derivative that reverses obesity-induced dysregulated glucose metabolism and hepatic lipotoxicity in genetic and dietary rodent models of obesity. The mechanism by which SEFA-1024 works may include increasing aGLP-1, promoting fatty acid oxidation, and inhibiting hepatic triglyceride formation. SEFA-1024 may serve as a potential treatment for obesity-related diabetes and NAFLD.

中文翻译：

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结构工程脂肪酸 1024 (SEFA-1024) 可改善饮食引起的肥胖、胰岛素抵抗和脂肪肝疾病

肥胖是一种全球流行病，导致心血管疾病、糖尿病和非酒精性脂肪肝 (NAFLD) 的发病率和死亡率增加。目前尚无明确的疗法被批准用于改善肥胖患者的血糖控制和治疗 NAFLD。在这里，我们研究了一种半合成、长链、结构工程脂肪酸-1024 (SEFA-1024)，作为啮齿动物模型中肥胖引起的高血糖、胰岛素抵抗和脂肪肝疾病的治疗方法。在存在和不存在 DPP-4 抑制剂的情况下，施用单剂量 SEFA-1024 来评估瘦大鼠的葡萄糖耐量和活性胰高血糖素样肽 1 (GLP-1)。SEFA-1024 对体重减轻和血糖控制的影响通过遗传（ob/ob）和环境（高脂肪饮食）肥胖小鼠模型。还在高脂饮食小鼠模型中评估了肝脏组织学、血清肝酶、肝脏脂质组学和肝脏基因表达。SEFA-1024 逆转了肥胖相关的胰岛素抵抗并改善了血糖控制。SEFA-1024 增加活性 GLP-1。在饮食引起的肥胖的长期模型中，SEFA-1024 逆转了体重过度增加、肝脏脂肪变性、肝酶升高、肝脂毒性，并促进脂肪酸代谢。SEFA-1024 是一种肠肝靶向二十碳五烯酸衍生物，可逆转肥胖遗传和饮食啮齿动物模型中肥胖引起的葡萄糖代谢失调和肝脂毒性。SEFA-1024 的作用机制可能包括增加 aGLP-1、促进脂肪酸氧化、并抑制肝脏甘油三酯的形成。SEFA-1024 可能作为肥胖相关糖尿病和 NAFLD 的潜在治疗方法。