Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism.
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(DeltaNES) mice). JNK1(DeltaNES) 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(DeltaNES) 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.
Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases and Center of Molecular Medicine Cologne, University of Cologne, D-50674 Cologne, Germany.
Bengt F
BF
Belgardt
Jan
J
Mauer
F Thomas
FT
Wunderlich
Marianne B
MB
Ernst
Martin
M
Pal
Gabriele
G
Spohn
Hella S
HS
Brönneke
Susanne
S
Brodesser
Brigitte
B
Hampel
Astrid C
AC
Schauss
Jens C
JC
Brüning
D050154:Adiposity / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000502:physiology; D004041:Dietary Fats / Q000008:administration & dosage; D005947:Glucose / Q000378:metabolism*; D013006:Growth Hormone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D010902:Pituitary Gland / Q000378:metabolism*; D015398:Signal Transduction; D013961:Thyroid Gland / Q000378:metabolism
D004041:Dietary Fats; D007328:Insulin; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D013006:Growth Hormone; D048055:Mitogen-Activated Protein Kinase 8; D005947:Glucose