期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 13, 页码 6028-6033出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1001796107
关键词
brain; diabetes; obesity; inflammation; insulin resistance
资金
- Center of Molecular Medicine Cologne
- European Union [LSHM-CT-2003-503041]
- Fritz Thyssen Stiftung [Az. 10.04.1.153, Az. 10.06.2.175]
- European Foundation for the Study of Diabetes/Lilly European Diabetes Research Programme
- German Research Foundation [Br. 1492/7-1]
- European Community [FP7/2007-2013, 201608]
c-Jun N-terminal kinase (JNK) 1-dependent signaling plays a crucial role in the development of obesity-associated insulin resistance. Here we demonstrate that JNK activation not only occurs in peripheral tissues, but also in the hypothalamus and pituitary of obese mice. To resolve the importance of JNK1 signaling in the hypothalamic/pituitary circuitry, we have generated mice with a conditional inactivation of JNK1 in nestin-expressing cells (JNK1(Delta NES) mice). JNK1(Delta NES) mice exhibit improved insulin sensitivity both in the CNS and in peripheral tissues, improved glucose metabolism, as well as protection from hepatic steatosis and adipose tissue dysfunction upon high-fat feeding. Moreover, JNK1(Delta NES) mice also show reduced somatic growth in the presence of reduced circulating growth hormone (GH) and insulin-like growth factor 1 (IGF1) concentrations, as well as increased thyroid axis activity. Collectively, these experiments reveal an unexpected, critical role for hypothalamic/pituitary JNK1 signaling in the coordination of metabolic/endocrine homeostasis.
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