UMMS Affiliation

Department of Medicine, Division of Endocrinology, Metabolism and Diabetes; Program in Molecular Medicine

Publication Date

2015-07-01

Document Type

Article

Subjects

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

Disciplines

Biochemistry | Cell Biology | Cellular and Molecular Physiology | Endocrinology | Molecular Biology

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.

Rights and Permissions

Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.

DOI of Published Version

10.1128/MCB.00150-15

Source

Mol Cell Biol. 2015 Jul;35(13):2356-65. Link to article on publisher's site

Journal/Book/Conference Title

Molecular and cellular biology

Related Resources

Link to Article in PubMed

PubMed ID

25918248

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