Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues
Authors
Danai, Laura V.Roth Flach, Rachel J.
Virbasius, Joseph V
Menendez, Lorena Garcia
Jung, Dae Young
Kim, Jong Hun
Kim, Jason K.
Czech, Michael P.
UMass Chan Affiliations
Program in Molecular MedicineDepartment of Medicine, Division of Endocrinology, Metabolism and Diabetes
Document Type
Journal ArticlePublication Date
2015-07-01Keywords
Adipose TissueAnimals
Blood Glucose
*Gene Deletion
Glucose
Insulin
Insulin Resistance
Liver
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Obese
Myogenic Regulatory Factor 5
Obesity
Protein-Serine-Threonine Kinases
Tamoxifen
Biochemistry
Cell Biology
Cellular and Molecular Physiology
Endocrinology
Molecular Biology
Metadata
Show full item recordAbstract
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.Source
Mol Cell Biol. 2015 Jul;35(13):2356-65. Link to article on publisher's siteDOI
10.1128/MCB.00150-15Permanent Link to this Item
http://hdl.handle.net/20.500.14038/44469PubMed ID
25918248Related Resources
Link to Article in PubMedRights
Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.
ae974a485f413a2113503eed53cd6c53
10.1128/MCB.00150-15