title: Forkhead Box O6 (FoxO6) Depletion Attenuates Hepatic Gluconeogenesis and Protects against Fat-induced Glucose Disorder in Mice.
abstract: Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. FoxO6 is a distinct member of the FoxO subfamily. To elucidate the role of FoxO6 in hepatic gluconeogenesis and assess its contribution to the pathogenesis of fasting hyperglycemia in diabetes, we generated FoxO6 knock-out (FoxO6-KO) mice followed by determining the effect of FoxO6 loss-of-function on hepatic gluconeogenesis under physiological and pathological conditions. FoxO6 depletion attenuated hepatic gluconeogenesis and lowered fasting glycemia in FoxO6-KO mice. FoxO6-deficient primary hepatocytes were associated with reduced capacities to produce glucose in response to glucagon. When fed a high fat diet, FoxO6-KO mice exhibited significantly enhanced glucose tolerance and reduced blood glucose levels accompanied by improved insulin sensitivity. These effects correlated with attenuated hepatic gluconeogenesis in FoxO6-KO mice. In contrast, wild-type littermates developed fat-induced glucose intolerance with a concomitant induction of fasting hyperinsulinemia and hyperglycemia. Furthermore, FoxO6-KO mice displayed significantly diminished macrophage infiltration into liver and adipose tissues, correlating with the reduction of macrophage expression of C-C chemokine receptor 2 (CCR2), a factor that is critical for regulating macrophage recruitment in peripheral tissues. Our data indicate that FoxO6 depletion protected against diet-induced glucose intolerance and insulin resistance by attenuating hepatic gluconeogenesis and curbing macrophage infiltration in liver and adipose tissues in mice.
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Virtu
authors.initials: V
authors.lastname: Calabuig-Navarro
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yamauchi
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Sojin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, 200433 Shanghai, China.
authors.forename: Yun-Zi
authors.initials: YZ
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Sadlek
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Coudriet
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Piganelli
authors.affiliation: Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, 200433 Shanghai, China.
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Rita
authors.initials: R
authors.lastname: Miller
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Mark
authors.initials: M
authors.lastname: Lowe
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224. Electronic address: dongh@pitt.edu.
authors.forename: H Henry
authors.initials: HH
authors.lastname: Dong
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D006943:Hyperglycemia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D006946:Hyperinsulinism / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism
chemical_list: C515335:Ccr2 protein, mouse; D004041:Dietary Fats; D051858:Forkhead Transcription Factors; C525395:Foxo6 protein, mouse; D054390:Receptors, CCR2
keywords: FoxO6; diabetes; gluconeogenesis; glucose metabolism; liver; mice; obesity