Leptin Reduces the Expression and Increases the Phosphorylation of the Negative Regulators of GLUT4 Traffic TBC1D1 and TBC1D4 in Muscle of ob/ob Mice

被引:21
作者
Sainz, Neira [1 ,4 ]
Rodriguez, Amaia [1 ,4 ]
Catalan, Victoria [1 ,4 ]
Becerril, Sara [1 ,4 ]
Ramirez, Beatriz [1 ,4 ]
Lancha, Andoni [1 ,4 ]
Burgos-Ramos, Emma [3 ,4 ]
Gomez-Ambrosi, Javier [1 ,4 ]
Fruehbeck, Gema [1 ,2 ,4 ]
机构
[1] Univ Navarra, Metab Res Lab, E-31080 Pamplona, Spain
[2] Univ Navarra Clin, Dept Endocrinol & Nutr, Pamplona, Spain
[3] Hosp Infantil Univ Nino Jesus, Dept Endocrinol, Madrid, Spain
[4] Inst Salud Carlos III, CIBER Fisiopatol Obesidad & Nutr CIBERobn, Pamplona, Spain
来源
PLOS ONE | 2012年 / 7卷 / 01期
关键词
RAT SKELETAL-MUSCLE; STIMULATED GLUCOSE-UPTAKE; FATTY-ACID OXIDATION; INSULIN SENSITIVITY; AS160; PHOSPHORYLATION; GENE-EXPRESSION; AKT SUBSTRATE; OBESE MICE; PROTEIN; TRANSLOCATION;
D O I
10.1371/journal.pone.0029389
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Leptin improves insulin sensitivity in skeletal muscle. Our goal was to determine whether proteins controlling GLUT4 traffic are altered by leptin deficiency and in vivo leptin administration in skeletal muscle of wild type and ob/ob mice. Leptin-deficient ob/ob mice were divided in three groups: control, leptin-treated (1 mg/kg/d) and leptin pair-fed ob/ob mice. Microarray analysis revealed that 1,546 and 1,127 genes were regulated by leptin deficiency and leptin treatment, respectively. Among these, we identified 24 genes involved in intracellular vesicle-mediated transport in ob/ob mice. TBC1 domain family, member 1 (Tbc1d1), a negative regulator of GLUT4 translocation, was up-regulated (P = 0.001) in ob/ob mice as compared to wild types. Importantly, leptin treatment reduced the transcript levels of Tbc1d1 (P < 0.001) and Tbc1d4 (P = 0.004) in the leptin-treated ob/ob as compared to pair-fed ob/ob animals. In addition, phosphorylation levels of TBC1D1 and TBC1D4 were enhanced in leptin-treated ob/ob as compared to control ob/ob (P = 0.015 and P = 0.023, respectively) and pair-fed ob/ob (P = 0.036 and P = 0.034, respectively) mice. Despite similar GLUT4 protein expression in wild type and ob/ob groups a different immunolocalization of this protein was evidenced in muscle sections. Leptin treatment increased GLUT4 immunoreactivity in gastrocnemius and extensor digitorum longus sections of leptin-treated ob/ob mice. Moreover, GLUT4 protein detected in immunoprecipitates from TBC1D4 was reduced by leptin replacement compared to control ob/ob (P = 0.013) and pair-fed ob/ob (P = 0.037) mice. Our findings suggest that leptin enhances the intracellular GLUT4 transport in skeletal muscle of ob/ob animals by reducing the expression and activity of the negative regulators of GLUT4 traffic TBC1D1 and TBC1D4.
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页数:12
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