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Publication
Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin
Sensitivity in Liver and Adipose Tissues.
Authors Danai LV, Flach RJ, Virbasius JV, Menendez LG, Jung DY, Kim JH, Kim JK, Czech MP
Submitted By Submitted Externally on 10/1/2015
Status Published
Journal Molecular and cellular biology
Year 2015
Date Published 7/1/2015
Volume : Pages 35 : 2356 - 65
PubMed Reference 25918248
Abstract Studies in vitro suggest that mitogen-activated protein kinase kinase kinase
kinase 4 (Map4k4) attenuates insulin signaling, but confirmation in vivo is
lacking since Map4k4 knockout is lethal during embryogenesis. We thus generated
mice with floxed Map4k4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase
under the control of the ubiquitin C promoter to induce whole-body Map4k4
deletion after these animals reached maturity. Tamoxifen administration to these
mice induced Map4k4 deletion in all tissues examined, causing decreased fasting
blood glucose concentrations and enhanced insulin signaling to AKT in adipose
tissue and liver but not in skeletal muscle. Surprisingly, however, mice
generated with a conditional Map4k4 deletion in adiponectin-positive adipocytes
or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes.
Instead, mice with Map4k4 deleted in Myf5-positive tissues, including all
skeletal muscles tested, were protected from obesity-induced glucose intolerance
and insulin resistance. Remarkably, these mice also showed increased insulin
sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic
phenotypes observed in inducible whole-body knockout mice. Taken together, these
results indicate that (i) Map4k4 controls a pathway in Myf5-positive cells that
suppresses whole-body insulin sensitivity and (ii) Map4k4 is a potential
therapeutic target for improving glucose tolerance and insulin sensitivity in
type 2 diabetes.






Genes
SymbolDescription
Map4k4mitogen-activated protein kinase kinase kinase kinase 4

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