Repository logo
 

DLK1/PREF1 regulates nutrient metabolism and protects from steatosis.


Type

Article

Change log

Authors

Charalambous, Marika 
Da Rocha, Simao Teixeira 
Radford, Elizabeth Jane 
Medina-Gomez, Gema 
Curran, Scott 

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.

Description

Keywords

Delta-like homologue 1, adipose tissue, genomic imprinting, growth hormone, hepatosteatosis, Animals, Calcium-Binding Proteins, Embryonic Development, Fatty Liver, Female, Insulin-Like Growth Factor I, Intercellular Signaling Peptides and Proteins, Lipid Metabolism, Mice, Mice, Transgenic, Pregnancy

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

111

Publisher

Proceedings of the National Academy of Sciences
Sponsorship
Medical Research Council (MC_UU_12012/2)
Medical Research Council (MR/J001597/1)
Medical Research Council (G0802051)
Medical Research Council (G0600717)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_UU_12012/5/B)
Wellcome Trust (095606/Z/11/Z)
Medical Research Council (MC_PC_12012)
Medical Research Council (G0600717/1)