title: DLK1/PREF1 regulates nutrient metabolism and protects from steatosis.
abstract: Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance and obesity, as well as progressive liver dysfunction. Recent animal studies have underscored the importance of hepatic growth hormone (GH) signaling in the development of NAFLD. The imprinted Delta-like homolog 1 (Dlk1)/preadipocyte factor 1 (Pref1) gene encodes a complex protein producing both circulating and membrane-tethered isoforms whose expression dosage is functionally important because even modest elevation during embryogenesis causes lethality. DLK1 is up-regulated during embryogenesis, during suckling, and in the mother during pregnancy. We investigated the normal role for elevated DLK1 dosage by overexpressing Dlk1 from endogenous control elements. This increased DLK1 dosage caused improved glucose tolerance with no primary defect in adipose tissue expansion even under extreme metabolic stress. Rather, Dlk1 overexpression caused reduced fat stores, pituitary insulin-like growth factor 1 (IGF1) resistance, and a defect in feedback regulation of GH. Increased circulatory GH culminated in a switch in whole body fuel metabolism and a reduction in hepatic steatosis. We propose that the function of DLK1 is to shift the metabolic mode of the organism toward peripheral lipid oxidation and away from lipid storage, thus mediating important physiological adaptations associated with early life and with implications for metabolic disease resistance.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom; and m.charalambous@qmul.ac.uk afsmith@mole.bio.cam.ac.uk.
authors.forename: Marika
authors.initials: M
authors.lastname: Charalambous
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom; and.
authors.forename: Simao Teixeira
authors.initials: ST
authors.lastname: Da Rocha
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom; and.
authors.forename: Elizabeth Jane
authors.initials: EJ
authors.lastname: Radford
authors.affiliation: Metabolic Research Laboratories, Wellcome Trust and Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QR, United Kingdom.
authors.forename: Gema
authors.initials: G
authors.lastname: Medina-Gomez
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom; and.
authors.forename: Scott
authors.initials: S
authors.lastname: Curran
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom; and.
authors.forename: Scarlett B
authors.initials: SB
authors.lastname: Pinnock
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom; and.
authors.forename: Sacri R
authors.initials: SR
authors.lastname: Ferrón
authors.affiliation: Metabolic Research Laboratories, Wellcome Trust and Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QR, United Kingdom.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom; and m.charalambous@qmul.ac.uk afsmith@mole.bio.cam.ac.uk.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ferguson-Smith
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D047108:Embryonic Development; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I
keywords: Delta-like homologue 1; adipose tissue; genomic imprinting; growth hormone; hepatosteatosis