title: Regulation of hepatic energy metabolism and gluconeogenesis by BAD.
abstract: The homeostatic balance of hepatic glucose utilization, storage, and production is exquisitely controlled by hormonal signals and hepatic carbon metabolism during fed and fasted states. How the liver senses extracellular glucose to cue glucose utilization versus production is not fully understood. We show that the physiologic balance of hepatic glycolysis and gluconeogenesis is regulated by Bcl-2-associated agonist of cell death (BAD), a protein with roles in apoptosis and metabolism. BAD deficiency reprograms hepatic substrate and energy metabolism toward diminished glycolysis, excess fatty acid oxidation, and exaggerated glucose production that escapes suppression by insulin. Genetic and biochemical evidence suggests that BAD's suppression of gluconeogenesis is actuated by phosphorylation of its BCL-2 homology (BH)-3 domain and subsequent activation of glucokinase. The physiologic relevance of these findings is evident from the ability of a BAD phosphomimic variant to counteract unrestrained gluconeogenesis and improve glycemia in leptin-resistant and high-fat diet models of diabetes and insulin resistance.
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Alfredo
authors: A
authors: Giménez-Cassina
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Luisa
authors: L
authors: Garcia-Haro
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA; Division of Endocrinology, Lee Gil Ya Cancer and Diabetes Institute, Gil Medical Center, Gachon University, Incheon 405-760, Korea.
authors: Cheol Soo
authors: CS
authors: Choi
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Mayowa A
authors: MA
authors: Osundiji
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Elizabeth A
authors: EA
authors: Lane
authors: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors: Hu
authors: H
authors: Huang
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Muhammed A
authors: MA
authors: Yildirim
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Benjamin
authors: B
authors: Szlyk
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Jill K
authors: JK
authors: Fisher
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Klaudia
authors: K
authors: Polak
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Elaura
authors: E
authors: Patton
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Jessica
authors: J
authors: Wiwczar
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Marina
authors: M
authors: Godes
authors: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors: Dae Ho
authors: DH
authors: Lee
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Kirsten
authors: K
authors: Robertson
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors: Sheene
authors: S
authors: Kim
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors: Ameya
authors: A
authors: Kulkarni
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors: Alberto
authors: A
authors: Distefano
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors: Varman
authors: V
authors: Samuel
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors: Gary
authors: G
authors: Cline
authors: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors: Young-Bum
authors: YB
authors: Kim
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
authors: Gerald I
authors: GI
authors: Shulman
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: nika_danial@dfci.harvard.edu.
authors: Nika N
authors: NN
authors: Danial
mesh_terms: D000818:Animals; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D005943:Gluconeogenesis / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051025:bcl-Associated Death Protein