Functional role of c-Jun-N-terminal kinase in feeding regulation.
c-Jun-N-terminal kinase (JNK) is a signaling molecule that is activated by proinflammatory signals, endoplasmic reticulum (ER) stress, and other environmental stressors. Although JNK has diverse effects on immunological responses and insulin resistance in peripheral tissues, a functional role for JNK in feeding regulation has not been established. In this study, we show that central inhibition of JNK activity potentiates the stimulatory effects of glucocorticoids on food intake and that this effect is abolished in mice whose agouti-related peptide (AgRP) neurons are degenerated. JNK1-deficient mice feed more upon central administration of glucocorticoids, and glucocorticoid receptor nuclear immunoreactivity is enhanced in the AgRP neurons. JNK inhibition in hypothalamic explants stimulates Agrp expression, and JNK1-deficient mice exhibit increased Agrp expression, heightened hyperphagia, and weight gain during refeeding. Our study shows that JNK1 is a novel regulator of feeding by antagonizing glucocorticoid function in AgRP neurons. Paradoxically, JNK1 mutant mice feed less and lose more weight upon central administration of insulin, suggesting that JNK1 antagonizes insulin function in the brain. Thus, JNK may integrate diverse metabolic signals and differentially regulate feeding under distinct physiological conditions.
Unger
Elizabeth K
EK
UCSF Diabetes Center, Department of Anatomy, University of California, San Francisco, California 94143, USA.
Piper
Merisa L
ML
Olofsson
Louise E
LE
Xu
Allison W
AW
D054369:Agouti-Related Protein / Q000235:genetics; D000818:Animals; D001066:Appetite / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D002149:Energy Intake / Q000187:drug effects / Q000502:physiology*; D017353:Gene Deletion; D006706:Homeostasis; D007031:Hypothalamus / Q000166:cytology / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics; D009478:Neuropeptide Y / Q000235:genetics; D011333:Pro-Opiomelanocortin / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D020738:Leptin; D008070:Lipopolysaccharides; D009478:Neuropeptide Y; D012333:RNA, Messenger; D011333:Pro-Opiomelanocortin; D003346:Corticotropin-Releasing Hormone; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8