GPRC5B-Mediated Sphingomyelin Synthase 2 Phosphorylation Plays a Critical Role in Insulin Resistance.

GPRC5B recruitment of Src family kinases has been implicated in diet-induced insulin resistance. However, the mechanism of this action is not fully understood. Here, we report that GPRC5B-mediated phosphorylation of sphingomyelin synthase 2 (SMS2) by Fyn is a crucial step in the development of insulin resistance. Lipid-induced metabolic stress augments SMS2 phosphorylation by facilitating the interaction of GPRC5B and SMS2. SMS2 phosphorylation reduces its ubiquitination, and consequently increases SMS2 protein abundance. Although ceramide and diacylglycerol (DAG) have been known to be central mediators of lipid-induced insulin resistance, the accumulation of these lipids fails to impair insulin signaling in SMS2 knockout mouse embryonic fibroblasts (MEFs). Conversely, exogenous expression of a phosphomimetic SMS2 impairs insulin action in SMS2 knockout MEFs under metabolic stress conditions. We demonstrate that SMS2-generated DAG in sphingomyelin synthesis inhibits insulin signaling through JNK activation. Thus, GPRC5B links sphingolipid metabolism to diet-induced insulin resistance via SMS2-dependent DAG production.