title: Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia.
abstract: Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of Map4k4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body Map4k4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced β cell mass, fewer proliferating β cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase Map4k4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from β cells in mice.
authors.affiliation: From the Program in Molecular Medicine.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Roth Flach
authors.affiliation: From the Program in Molecular Medicine.
authors.forename: Laura V
authors.initials: LV
authors.lastname: Danai
authors.affiliation: From the Program in Molecular Medicine.
authors.forename: Marina T
authors.initials: MT
authors.lastname: DiStefano
authors.affiliation: Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Mark
authors.initials: M
authors.lastname: Kelly
authors.affiliation: From the Program in Molecular Medicine.
authors.forename: Lorena Garcia
authors.initials: LG
authors.lastname: Menendez
authors.affiliation: From the Program in Molecular Medicine.
authors.forename: Agata
authors.initials: A
authors.lastname: Jurczyk
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, and.
authors.forename: Rohit B
authors.initials: RB
authors.lastname: Sharma
authors.affiliation: From the Program in Molecular Medicine.
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.affiliation: From the Program in Molecular Medicine.
authors.forename: Jong Hun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: From the Program in Molecular Medicine, Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, and.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: From the Program in Molecular Medicine.
authors.forename: Rita
authors.initials: R
authors.lastname: Bortell
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, and.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Alonso
authors.affiliation: From the Program in Molecular Medicine, Michael.Czech@umassmed.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D004041:Dietary Fats; D007328:Insulin; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C532752:S961 peptide
keywords: diabetes; insulin; mitogen-activated protein kinase (MAPK); pancreas; pancreatic islet