Research Resource: Roles for Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) in Systems Metabolism
Autor: | Christopher B. Newgard, Anna Tsimelzon, Susan G. Hilsenbeck, Robert Stevens, Olga Ilkayeva, James R. Bain, Anthony R. Means, Thomas J. Ribar, Brian York, Christopher R. Means, Kathrina L. Marcelo |
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Rok vydání: | 2016 |
Předmět: |
Male
0301 basic medicine medicine.medical_specialty Calmodulin Calcium-Calmodulin-Dependent Protein Kinase Kinase 030209 endocrinology & metabolism Biology Diet High-Fat Endoplasmic Reticulum Mice Plasma 03 medical and health sciences 0302 clinical medicine Endocrinology Insulin resistance Insulin-Secreting Cells Ca2+/calmodulin-dependent protein kinase Internal medicine medicine Animals Insulin Research Resource ASK1 Amino Acids Muscle Skeletal Protein kinase A Molecular Biology CAMKK2 Fatty Acids General Medicine medicine.disease Cell biology Mice Inbred C57BL Insulin receptor Glucose 030104 developmental biology Liver biology.protein Calcium Insulin Resistance Signal transduction Signal Transduction |
Zdroj: | Molecular Endocrinology. 30:557-572 |
ISSN: | 1944-9917 0888-8809 |
Popis: | A number of epidemiological studies have implicated calcium (Ca(2+)) signaling as a major factor in obesity that contributes to aberrant systems metabolism. Somewhat paradoxically, obesity correlates with decreased circulating Ca(2+) levels, leading to increased release of intracellular Ca(2+) stores from the endoplasmic reticulum. These findings suggest that insulin resistance associated with the obese state is linked to activation of canonical Ca(2+) signaling pathways. Mechanistically, increased intracellular Ca(2+) binds calmodulin (CaM) to activate a set of Ca(2+)/CaM-dependent protein kinases. In this research resource, we explore the metabolic functions and implications of Ca(2+)/CaM-dependent protein kinase kinase 2 (CaMKK2) as a metabolic effector of Ca(2+)/CaM action. We reveal the importance of CaMKK2 for gating insulin release from pancreatic β-cells while concomitantly influencing the sensitivity of insulin-responsive tissues. To provide a better understanding of the metabolic impact of CaMKK2 loss, we performed targeted metabolomic analyses of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice null for CaMKK2. We quantified amino acids and acyl carnitines in 3 insulin-sensitive tissues (liver, skeletal muscle, plasma) isolated from CaMKK2(-/-) mice and their wild-type littermates under conditions of dietary stress (low-fat diet, normal chow, high-fat diet, and fasting), thereby unveiling unique metabolic functions of CaMKK2. Our findings highlight CaMKK2 as a molecular rheostat for insulin action and emphasize the importance of Ca(2+)/CaM/CaMKK2 in regulation of whole-body metabolism. These findings reveal that CaMKK2 may be an attractive therapeutic target for combatting comorbidities associated with perturbed insulin signaling. |
Databáze: | OpenAIRE |
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