Role of transcription factor NFAT in glucose and insulin homeostasis.
Compromised immunoregulation contributes to obesity and complications in metabolic pathogenesis. Here, we demonstrate that the nuclear factor of activated T cell (NFAT) group of transcription factors contributes to glucose and insulin homeostasis. Expression of two members of the NFAT family (NFATc2 and NFATc4) is induced upon adipogenesis and in obese mice. Mice with the Nfatc2-/- Nfatc4-/- compound disruption exhibit defects in fat accumulation and are lean. Nfatc2-/- Nfatc4-/- mice are also protected from diet-induced obesity. Ablation of NFATc2 and NFATc4 increases insulin sensitivity, in part, by sustained activation of the insulin signaling pathway. Nfatc2-/- Nfatc4-/- mice also exhibit an altered adipokine profile, with reduced resistin and leptin levels. Mechanistically, NFAT is recruited to the transcription loci and regulates resistin gene expression upon insulin stimulation. Together, these results establish a role for NFAT in glucose/insulin homeostasis and expand the repertoire of NFAT function to metabolic pathogenesis and adipokine gene transcription.
Yang
Teddy T C
TT
Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Suk
Hee Yun
HY
Yang
Xiaoyong
X
Olabisi
Opeyemi
O
Yu
Raymond Y L
RY
Durand
Jorge
J
Jelicks
Linda A
LA
Kim
Ja-Young
JY
Scherer
Philipp E
PE
Wang
Yuhua
Y
Feng
Yun
Y
Rossetti
Luciano
L
Graef
Isabella A
IA
Crabtree
Gerald R
GR
Chow
Chi-Wing
CW
D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002522:Chlorocebus aethiops; D004041:Dietary Fats / Q000494:pharmacology; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D052243:Resistin / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction
D004041:Dietary Fats; D007328:Insulin; D009097:Multienzyme Complexes; D050778:NFATC Transcription Factors; D052243:Resistin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose