Gene expression profiles in epididymal white adipose tissue of lysophosphatidic acid receptor 4-KO mice

White adipose tissue (WAT) is a highly active metabolic and endocrine organ, and its dysfunction links obesity to a variety of diseases, ranging from type 2 diabetes to cancer. The function of WAT is under the control of multiple cell signaling systems, including that of G protein-coupled receptors (GPCRs). Gs- and Gi-coupled receptors have been reported to regulate lipolysis, and Gq-coupled receptors stimulate glucose uptake in adipocytes. However, the roles of G12/13-coupled receptors in WAT are totally unknown. Here we show that lysophosphatidic acid receptor 4 (LPA4), an adipose cluster GPCR, selectively activates G12/13 proteins in adipocytes, and limits continuous remodeling and healthy expansion of WAT in mice. Under standard diet conditions, LPA4-knockout mice showed higher expression levels of mitochondrial biogenesis-related genes in WAT, along with higher production of adiponectin than control mice. In vitro studies have consistently demonstrated that the LPA4/Rho/Rho-kinase signaling pathway suppresses mRNA expression of mitochondrial biogenesis-related genes in adipocytes. In a diet-induced obesity model, LPA4-deficient mice showed metabolically healthy obese phenotypes, with continuous WAT expansion, and protection from WAT inflammation, hepatosteatosis, and insulin resistance. Given that GPCRs comprise the most successful class of drug targets, LPA4 would be a promising therapeutic target for obesity-related metabolic disorders.

8

Yanagida K, Igarashi H, Yasuda D, Kobayashi D, Ohto-Nakanishi T, Akahoshi N, Sekiba A, Toyoda T, Ishijima T, Nakai Y, Shojima N, Kubota N, Abe K, Kadowaki T, Ishii S, Shimizu T