Functional Roles of Proline/Arginine-Rich End Leucine-Rich Repeat Protein (PRELP) in Adipocytes

Abstract

Adipose tissue fibrosis is recognized as a hallmark of adipose tissue dysfunction. We have previously identified PRELP as a novel regulator of adipogenesis by using lentiviral short hairpin RNA libraries targeting murine genomes. PRELP belongs to the family of leucine-rich repeat proteins, which are characterized by a series of adjacent leucine-rich motifs flanked by disulfide-bounded domains. Functionally, PRELP anchors basement membranes to connective tissues. However, roles of PRELP in adipocytes remain unclear. In the present study, we show that PRELP expression is up-regulated both in adipocytes of high-fat diet induced obesity mice and ob/ob mice. PRELP reduction in 3T3-L1 adipocytes leads to enhanced insulin signaling and insulin-stimulated glucose uptake. To determine functions of PRELP in the development of metabolic phenotypes, we generated adipocyte-specific PRELP transgenic mice. Adipose-specific overexpression of PRELP results in the development of significant adipose tissue fibrosis and insulin resistance on high fat diet without difference of body weight and adiposity. This phenotype is associated with increased expression of inflammation genes and decreased insulin signaling in adipose tissue of PRELP transgenic mice. Furthermore, we find that global Prelp deficient mice are protected from adipose tissue fibrosis and insulin resistance associated with high fat feeding. These data suggest that PRELP might play a key role in the development of adipose tissue remodeling in obesity. Disclosure J. Eguchi: None. J. Wada: None.