Altered energy homeostasis and resistance to diet-induced obesity in KRAP-deficient mice.
Altered energy homeostasis and resistance to diet-induced obesity in KRAP-deficient mice.
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DOI：
10.1371/journal.pone.0004240
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Shirasawa, Senji
中科院分区：
文献类型：
--
作者：
Fujimoto, Takahiro;Miyasaka, Kyoko;Koyanagi, Midori;Tsunoda, Toshiyuki;Baba, Iwai;Doi, Keiko;Ohta, Minoru;Kato, Norihiro;Sasazuki, Takehiko;Shirasawa, Senji
肥胖和相关代谢紊乱已成为成人发病和死亡的主要原因。KRAP （ki -ras诱导的肌动蛋白相互作用蛋白）是一种细胞骨架相关蛋白，是组织中普遍存在的蛋白，最初被确定为癌症相关分子，但其生理作用尚不清楚。在这里，我们证明了KRAP- / -缺陷（KRAP - / -）小鼠表现出代谢率增强，脂肪减少，糖耐量改善，低胰岛素血症和低肽血症。KRAP - / -小鼠也被保护免受高脂肪饮食引起的肥胖和胰岛素抵抗，尽管有贪食。值得注意的是，KRAP - / -小鼠棕色脂肪组织（BAT）中的葡萄糖摄取以胰岛素不依赖的方式增强，这表明BAT参与了KRAP - / -小鼠能量稳态的改变，尽管UCP（解偶联蛋白）的表达没有改变。令人感兴趣的是脂肪酸代谢相关分子，包括乙酰辅酶a羧化酶(ACC)-1、ACC-2和脂肪酸合成酶在KRAP - / -小鼠肝脏中的下调，这可能部分解释了KRAP - / -小鼠的代谢表型。因此，KRAP是一种新的全身能量稳态调节因子，可能是肥胖及相关疾病的治疗靶点。
Obesity and related metabolic disorders have become leading causes of adult morbidity and mortality. KRAP (Ki-ras-induced actin-interacting protein) is a cytoskeleton-associated protein and a ubiquitous protein among tissues, originally identified as a cancer-related molecule, however, its physiological roles remain unknown. Here we demonstrate that KRAP-deficient (KRAP−/−) mice show enhanced metabolic rate, decreased adiposity, improved glucose tolerance, hypoinsulinemia and hypoleptinemia. KRAP−/− mice are also protected against high-fat diet-induced obesity and insulin resistance despite of hyperphagia. Notably, glucose uptake in the brown adipose tissue (BAT) in KRAP−/− mice is enhanced in an insulin-independent manner, suggesting that BAT is involved in altered energy homeostasis in KRAP−/− mice, although UCP (Uncoupling protein) expressions are not altered. Of interest is the down-regulation of fatty acid metabolism-related molecules, including acetyl-CoA carboxylase (ACC)-1, ACC-2 and fatty acid synthase in the liver of KRAP −/− mice, which could in part account for the metabolic phenotype in KRAP−/− mice. Thus, KRAP is a novel regulator in whole-body energy homeostasis and may be a therapeutic target in obesity and related diseases.
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