title: Hepatic mitogen-activated protein kinase phosphatase 1 selectively regulates glucose metabolism and energy homeostasis.
abstract: The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Lawan
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Gatzke
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Kisuk
authors.initials: K
authors.lastname: Min
authors.affiliation: Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Mashael
authors.initials: M
authors.lastname: Al-Mutairi
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Patric
authors.initials: P
authors.lastname: Richter
authors.affiliation: Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Joao Paulo G
authors.initials: JP
authors.lastname: Camporez
authors.affiliation: Cell Signaling Technology Incorporated, Danvers, Massachusetts, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Couvillon
authors.affiliation: Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Dominik
authors.initials: D
authors.lastname: Pesta
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Roth Flach
authors.affiliation: Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA anton.bennett@yale.edu.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Bennett
mesh_terms: D000483:Alleles; D000818:Animals; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004734:Energy Metabolism; D005234:Fatty Liver / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology; D006706:Homeostasis; D008099:Liver / Q000201:enzymology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D010101:Oxygen Consumption; D010766:Phosphorylation; D019076:Transgenes
chemical_list: C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D005947:Glucose