Increased serum leptin protects from adiposity despite the increased glucose uptake in white adipose tissue in mice lacking p85alpha phosphoinositide 3-kinase.
Increased serum leptin protects from adiposity despite the increased glucose uptake in white adipose tissue in mice lacking p85alpha phosphoinositide 3-kinase.
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DOI：
10.2337/diabetes.53.9.2261
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发表时间：
2004-09
期刊：
影响因子：
7.7
通讯作者：
Y. Terauchi;J. Matsui;J. Kamon;T. Yamauchi;N. Kubota;K. Komeda;S. Aizawa;Y. Akanuma;Motowo Tomita;T. Kadowaki
中科院分区：
文献类型：
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作者：
Y. Terauchi;J. Matsui;J. Kamon;T. Yamauchi;N. Kubota;K. Komeda;S. Aizawa;Y. Akanuma;Motowo Tomita;T. Kadowaki
缺乏p85pha调节亚基的磷脂酰肌醇(PI)3-激酶(Pik3r1(-/-))的小鼠，由于磷脂酰肌醇(3，4，5)-三磷酸[PtdIns(3，4，5)P3]的产生增加，白色脂肪组织(WAT)和骨骼肌中的葡萄糖摄取增加，而正常饮食的小鼠的体重和脂肪质量与野生型小鼠相似。在高脂饮食3个月后，Pik3r1(-/-)小鼠的胰岛素敏感性和葡萄糖耐量仍高于野生型小鼠，但体重和Wat质量的增加明显大于野生型小鼠。在正常饮食下，Pik3r1(-/-)小鼠的血清瘦素水平显著高于野生型小鼠，这是由于脂肪细胞分泌的瘦素增加，可能是由于脂肪细胞中PtdIns(3，4，5)P3的产生增加所致。瘦素(每天5微克/克体重)导致野生型小鼠和Pik3r1(-/-)小鼠的摄食量减少和体重减轻，这表明Pik3r1(-/-)小鼠对瘦素的敏感性与野生型小鼠相似。略微增加的血清瘦素补偿了Pik3r1(-/-)小鼠脂肪细胞增加的葡萄糖摄取，从而防止了正常饮食中的肥胖。在高脂饮食中，瘦素(每天5微克/克体重)在两种基因型中都没有减少摄食量或体重，表明这两种基因型确实已经变得严重的瘦素抵抗。因此，瘦素分泌不能充分补偿高脂饮食引起的严重瘦素抵抗，从而无法预防Pik3r1(-/-)小鼠的肥胖。我们的发现表明，正常饮食中血清瘦素的主要增加在防止Pik3r1(-/-)小鼠肥胖方面发挥了作用。
Mice lacking the p85alpha regulatory subunit of phosphoinositide (PI) 3-kinase (Pik3r1(-/-)) showed increased glucose uptake in white adipose tissue (WAT) and skeletal muscle due to increased phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P3] production and on a normal diet had a body weight and fat mass similar to wild-type mice. After 3 months on a high-fat diet, Pik3r1(-/-) mice still had increased insulin sensitivity and better glucose tolerance than wild-type mice, but showed markedly greater increases in body weight and WAT mass than wild-type mice. On the normal diet, serum leptin levels of Pik3r1(-/-) mice were significantly higher than in wild-type mice as a result of increased leptin secretion from adipocytes, presumably due to the increased PtdIns(3,4,5)P3 production in adipocytes. Leptin (5 microg/g body wt per day) caused a reduction in food intake and decrease in body weight by the wild-type mice as well as Pik3r1(-/-) mice, suggesting Pik3r1(-/-) mice having leptin sensitivity similar to wild-type mice. The slightly increased serum leptin compensated for the increased glucose uptake by adipocytes in Pik3r1(-/-) mice, thereby preventing adiposity on the normal diet. On the high-fat diet, leptin (5 microg/g body wt per day) failed to decrease food intake or body weight in either genotype, indicating that both genotypes had indeed become severely leptin resistant. Consequently, leptin secretion was unable to sufficiently compensate for the severe leptin resistance caused by the high-fat diet, thereby failing to prevent obesity in Pik3r1(-/-) mice. Our findings suggest that primary increase in serum leptin on the normal diet play a role in the protection from adiposity in Pik3r1(-/-) mice.