title: Adipocyte JAK2 mediates growth hormone-induced hepatic insulin resistance.
abstract: For nearly 100 years, growth hormone (GH) has been known to affect insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes. Here, we induce adipocyte-specific GHI through conditional deletion ofJak2(JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyteJak2augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extrahepatic, adipose tissue-dependent mechanism.
authors.affiliation: Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Corbit
authors.affiliation: Department of Internal Medicine.
authors.forename: João Paulo G
authors.initials: JPG
authors.lastname: Camporez
authors.affiliation: Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Tran
authors.affiliation: Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
authors.forename: Camella G
authors.initials: CG
authors.lastname: Wilson
authors.affiliation: Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
authors.forename: Dylan A
authors.initials: DA
authors.lastname: Lowe
authors.affiliation: Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nordstrom
authors.affiliation: Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
authors.forename: Kirthana
authors.initials: K
authors.lastname: Ganeshan
authors.affiliation: Department of Internal Medicine.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Perry
authors.affiliation: Department of Internal Medicine.|Cellular and Molecular Physiology, and.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.affiliation: Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Weiss
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D013006:Growth Hormone / Q000009:adverse effects*; D007333:Insulin Resistance; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological
chemical_list: D013006:Growth Hormone; C507924:JAK2 protein, human; D053614:Janus Kinase 2