DLK1/PREF1 regulates nutrient metabolism and protects from steatosis

TLDR

Nonalcoholic fatty liver disease is linked to insulin resistance, obesity, and progressive liver dysfunction, and hepatic growth hormone signaling—mediated in part by the imprinted DLK1/PREF1 gene—has been shown in animal studies to be crucial for its development. The study aimed to determine how elevated DLK1 dosage affects metabolism by overexpressing Dlk1 from its endogenous regulatory elements and to propose that DLK1 shifts the organism toward peripheral lipid oxidation, reducing lipid storage and protecting against steatosis. The authors overexpressed Dlk1 using its endogenous control elements to assess the effects of increased DLK1 dosage on glucose tolerance, adiposity, GH signaling, and hepatic steatosis. Elevated DLK1 dosage improved glucose tolerance, reduced fat stores, induced pituitary IGF1 resistance and GH feedback defects, increased circulating GH, shifted whole‑body fuel metabolism, and ultimately decreased hepatic 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.