Department of Medicine, Division of Endocrinology, Metabolism and Diabetes; Program in Molecular Medicine
Adipose Tissue; Animals; 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
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.
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DOI of Published Version
Mol Cell Biol. 2015 Jul;35(13):2356-65. Link to article on publisher's site
Molecular and cellular biology
Danai, Laura V.; Roth Flach, Rachel J.; Virbasius, Joseph V; Menendez, Lorena Garcia; Jung, Dae Young; Kim, Jong Hun; Kim, Jason K.; and Czech, Michael P., "Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues" (2015). Program in Molecular Medicine Publications and Presentations. 63.