Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice.
Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice.
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DOI：
10.1042/bj20110512
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发表时间：
2012-01-01
期刊：
影响因子：
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通讯作者：
Ashford ML
中科院分区：
文献类型：
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作者：
Meakin PJ;Harper AJ;Hamilton DL;Gallagher J;McNeilly AD;Burgess LA;Vaanholt LM;Bannon KA;Latcham J;Hussain I;Speakman JR;Howlett DR;Ashford ML
胰岛素抵抗和葡萄糖稳态受损是2型糖尿病的重要指标，也是AD（阿尔茨海默病）的早期危险因素。AD病理学的一个基本特征是存在BACE 1（β位点淀粉样前体蛋白裂解酶1），其调节毒性淀粉样肽的产生。然而，BACE 1是否也在葡萄糖体内平衡中发挥作用目前尚不清楚。我们使用转基因小鼠来分析BACE 1缺失对体重以及脂质和葡萄糖稳态的影响。BACE 1 −/−小鼠比野生型同窝小鼠更瘦，肥胖减少，能量消耗更高，葡萄糖处理和外周胰岛素敏感性改善。BACE 1 −/−小鼠也可以免受饮食诱导的肥胖。BACE 1缺乏的骨骼肌和肝脏表现出改善的胰岛素敏感性。在骨骼肌细胞系中，BACE 1抑制增加葡萄糖摄取并增强胰岛素敏感性。BACE 1的丢失与BAT（棕色脂肪组织）中UCP 1（解偶联蛋白1）和骨骼肌中UCP 2和UCP 3 mRNA水平升高相关，表明解偶联呼吸和代谢效率降低。因此，BACE 1水平可能在慢性营养过剩条件下的葡萄糖和脂质体内平衡中起关键作用。因此，改善BACE 1活性的策略可能是治疗糖尿病的重要新方法。
Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1−/− mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1−/− mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes.