title: Research Resource: Roles for Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) in Systems Metabolism.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Biology (K.L.M., A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030; Departments of Cell, Pharmacology and Cancer Biology (T.R.), Duke University School of Medicine, Durham, North Carolina 27710; Mouse Behavior and Neuroendocrine Analysis Core Facility (C.R.M.), Duke University School of Medicine, Durham, North Carolina 27710; Lester and Sue Smith Breast Center (A.T., S.G.H.), Baylor College of Medicine, Houston, Texas 77030; Sarah W. Stedman Nutrition and Metabolism Center (R.D.S., O.I., J.R.B., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710; and Dan L. Duncan Cancer Center (A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Kathrina L
authors.initials: KL
authors.lastname: Marcelo
authors.affiliation: Department of Molecular and Cellular Biology (K.L.M., A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030; Departments of Cell, Pharmacology and Cancer Biology (T.R.), Duke University School of Medicine, Durham, North Carolina 27710; Mouse Behavior and Neuroendocrine Analysis Core Facility (C.R.M.), Duke University School of Medicine, Durham, North Carolina 27710; Lester and Sue Smith Breast Center (A.T., S.G.H.), Baylor College of Medicine, Houston, Texas 77030; Sarah W. Stedman Nutrition and Metabolism Center (R.D.S., O.I., J.R.B., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710; and Dan L. Duncan Cancer Center (A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ribar
authors.affiliation: Department of Molecular and Cellular Biology (K.L.M., A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030; Departments of Cell, Pharmacology and Cancer Biology (T.R.), Duke University School of Medicine, Durham, North Carolina 27710; Mouse Behavior and Neuroendocrine Analysis Core Facility (C.R.M.), Duke University School of Medicine, Durham, North Carolina 27710; Lester and Sue Smith Breast Center (A.T., S.G.H.), Baylor College of Medicine, Houston, Texas 77030; Sarah W. Stedman Nutrition and Metabolism Center (R.D.S., O.I., J.R.B., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710; and Dan L. Duncan Cancer Center (A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Means
authors.affiliation: Department of Molecular and Cellular Biology (K.L.M., A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030; Departments of Cell, Pharmacology and Cancer Biology (T.R.), Duke University School of Medicine, Durham, North Carolina 27710; Mouse Behavior and Neuroendocrine Analysis Core Facility (C.R.M.), Duke University School of Medicine, Durham, North Carolina 27710; Lester and Sue Smith Breast Center (A.T., S.G.H.), Baylor College of Medicine, Houston, Texas 77030; Sarah W. Stedman Nutrition and Metabolism Center (R.D.S., O.I., J.R.B., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710; and Dan L. Duncan Cancer Center (A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.affiliation: Department of Molecular and Cellular Biology (K.L.M., A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030; Departments of Cell, Pharmacology and Cancer Biology (T.R.), Duke University School of Medicine, Durham, North Carolina 27710; Mouse Behavior and Neuroendocrine Analysis Core Facility (C.R.M.), Duke University School of Medicine, Durham, North Carolina 27710; Lester and Sue Smith Breast Center (A.T., S.G.H.), Baylor College of Medicine, Houston, Texas 77030; Sarah W. Stedman Nutrition and Metabolism Center (R.D.S., O.I., J.R.B., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710; and Dan L. Duncan Cancer Center (A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.affiliation: Department of Molecular and Cellular Biology (K.L.M., A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030; Departments of Cell, Pharmacology and Cancer Biology (T.R.), Duke University School of Medicine, Durham, North Carolina 27710; Mouse Behavior and Neuroendocrine Analysis Core Facility (C.R.M.), Duke University School of Medicine, Durham, North Carolina 27710; Lester and Sue Smith Breast Center (A.T., S.G.H.), Baylor College of Medicine, Houston, Texas 77030; Sarah W. Stedman Nutrition and Metabolism Center (R.D.S., O.I., J.R.B., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710; and Dan L. Duncan Cancer Center (A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Olga
authors.initials: O
authors.lastname: Ilkayeva
authors.affiliation: Department of Molecular and Cellular Biology (K.L.M., A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030; Departments of Cell, Pharmacology and Cancer Biology (T.R.), Duke University School of Medicine, Durham, North Carolina 27710; Mouse Behavior and Neuroendocrine Analysis Core Facility (C.R.M.), Duke University School of Medicine, Durham, North Carolina 27710; Lester and Sue Smith Breast Center (A.T., S.G.H.), Baylor College of Medicine, Houston, Texas 77030; Sarah W. Stedman Nutrition and Metabolism Center (R.D.S., O.I., J.R.B., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710; and Dan L. Duncan Cancer Center (A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: James R
authors.initials: JR
authors.lastname: Bain
authors.affiliation: Department of Molecular and Cellular Biology (K.L.M., A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030; Departments of Cell, Pharmacology and Cancer Biology (T.R.), Duke University School of Medicine, Durham, North Carolina 27710; Mouse Behavior and Neuroendocrine Analysis Core Facility (C.R.M.), Duke University School of Medicine, Durham, North Carolina 27710; Lester and Sue Smith Breast Center (A.T., S.G.H.), Baylor College of Medicine, Houston, Texas 77030; Sarah W. Stedman Nutrition and Metabolism Center (R.D.S., O.I., J.R.B., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710; and Dan L. Duncan Cancer Center (A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.affiliation: Department of Molecular and Cellular Biology (K.L.M., A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030; Departments of Cell, Pharmacology and Cancer Biology (T.R.), Duke University School of Medicine, Durham, North Carolina 27710; Mouse Behavior and Neuroendocrine Analysis Core Facility (C.R.M.), Duke University School of Medicine, Durham, North Carolina 27710; Lester and Sue Smith Breast Center (A.T., S.G.H.), Baylor College of Medicine, Houston, Texas 77030; Sarah W. Stedman Nutrition and Metabolism Center (R.D.S., O.I., J.R.B., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710; and Dan L. Duncan Cancer Center (A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Department of Molecular and Cellular Biology (K.L.M., A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030; Departments of Cell, Pharmacology and Cancer Biology (T.R.), Duke University School of Medicine, Durham, North Carolina 27710; Mouse Behavior and Neuroendocrine Analysis Core Facility (C.R.M.), Duke University School of Medicine, Durham, North Carolina 27710; Lester and Sue Smith Breast Center (A.T., S.G.H.), Baylor College of Medicine, Houston, Texas 77030; Sarah W. Stedman Nutrition and Metabolism Center (R.D.S., O.I., J.R.B., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710; and Dan L. Duncan Cancer Center (A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Means
authors.affiliation: Department of Molecular and Cellular Biology (K.L.M., A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030; Departments of Cell, Pharmacology and Cancer Biology (T.R.), Duke University School of Medicine, Durham, North Carolina 27710; Mouse Behavior and Neuroendocrine Analysis Core Facility (C.R.M.), Duke University School of Medicine, Durham, North Carolina 27710; Lester and Sue Smith Breast Center (A.T., S.G.H.), Baylor College of Medicine, Houston, Texas 77030; Sarah W. Stedman Nutrition and Metabolism Center (R.D.S., O.I., J.R.B., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710; and Dan L. Duncan Cancer Center (A.R.M., B.Y.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Brian
authors.initials: B
authors.lastname: York
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D059305:Diet, High-Fat / Q000379:methods; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D010949:Plasma / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000596:Amino Acids; D002147:Calmodulin; D005227:Fatty Acids; D007328:Insulin; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C517700:Camkk2 protein, mouse; D005947:Glucose; D002118:Calcium