Obesity and Comorbidities Research Center (OCRC), Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil.
Educational Union of Cascavel, UNIVEL, Cascavel, Parana, Brazil.
Food Res Int. 2022 Jun;156:111331. doi: 10.1016/j.foodres.2022.111331. Epub 2022 May 6.
Early childhood malnutrition may facilitate the onset of obesity and diabetes mellitus in adulthood which, when established, makes it more resistant to therapeutic interventions. The beneficial effects of tauroursodeoxycholic acid (TUDCA) in glucose homeostasis and body fat accumulation were analyzed in protein-restricted mice fed a high-fat diet (HFD). C57BL/6 mice were fed a control (14% protein [C]) or a protein-restricted (6% protein [R]) diet for 6 weeks. Afterward, mice received an HFD or not for 12 weeks (C mice fed an HFD [CH] and R mice fed an HFD [RH]). In the last 15 days of this period, half of the mice fed a HFD received i.p. PBS (groups CH and RH) or 300 mg/kg TUDCA (groups CHT and RHT). RH mice developed obesity, as demonstrated by the increase in fat accumulation, liver steatosis, and metabolic inflexibility. Additionally, showed glucose intolerance and insulin hypersecretion. TUDCA reduced adiposity and improve metabolic flexibility through increased HSL phosphorylation and CPT1 expression in eWAT and BAT, and reduced ectopic fat deposition by activating the AMPK/HSL pathway in the liver. Also, improved glucose tolerance and insulin sensitivity, normalizing insulin secretion by reducing GDH expression and increasing insulin peripheral sensitivity by greater expression of the IRβ in muscle and adipose tissue and reducing PEPCK liver expression. Our data indicate that TUDCA reduces global adiposity and improves glucose tolerance and insulin sensitivity in protein malnourished mice fed a HFD. Therefore, this is a possible strategy to reverse metabolic disorders in individuals with the double burden of malnutrition.
早期儿童营养不良可能会促进成年期肥胖和糖尿病的发生，而一旦发生，这些疾病就更难通过治疗干预来治愈。本研究旨在分析牛磺熊脱氧胆酸（TUDCA）在限制蛋白饮食（6%蛋白，R 饮食）喂养的高脂肪饮食（HFD）小鼠的葡萄糖稳态和体脂积累中的作用。C57BL/6 小鼠首先接受 6 周的对照饮食（14%蛋白，C 饮食）或限制蛋白饮食（6%蛋白，R 饮食），然后接受 12 周的 HFD 或不接受 HFD（C 饮食喂养 HFD[CH]和 R 饮食喂养 HFD[RH]）。在此期间的最后 15 天，一半接受 HFD 的小鼠接受腹腔注射 PBS（CH 和 RH 组）或 300mg/kg TUDCA（CHT 和 RHT 组）。RH 组小鼠发生肥胖，表现为脂肪堆积、肝脂肪变性和代谢灵活性降低。此外，还表现出葡萄糖不耐受和胰岛素分泌过多。TUDCA 通过增加 HSL 磷酸化和 CPT1 在 eWAT 和 BAT 中的表达，减少异位脂肪沉积，通过激活肝脏中的 AMPK/HSL 通路，降低脂肪含量，改善代谢灵活性。此外，还改善了葡萄糖耐量和胰岛素敏感性，通过降低 GDH 表达和增加肌肉和脂肪组织中 IRβ 的表达，以及通过降低肝脏中 PEPCK 的表达来增加胰岛素外周敏感性，从而使胰岛素分泌正常化。我们的数据表明，TUDCA 可降低 HFD 喂养的蛋白质营养不良小鼠的全身肥胖程度，并改善其葡萄糖耐量和胰岛素敏感性。因此，这是一种逆转具有营养不良双重负担的个体代谢紊乱的可能策略。
