14-3-3ζ regulates lipolysis by influencing adipocyte maturity

Abstract

One of the primary metabolic functions of a mature adipocyte is to supply energy via lipolysis, or the catabolism of stored lipids. Hormone-sensitive lipase (HSL) is a critical lipolytic enzyme, and its phosphorylation and subsequent activation by PKA generates phospho-binding sites for 14-3-3 proteins, a ubiquitously expressed family of molecular scaffolds. While we previously identified essential roles of the 14-3-3{zeta} isoform in murine adipogenesis, the presence of 14-3-3 protein binding sites on HSL suggests that 14-3-3{zeta} could also influence mature adipocyte processes like lipolysis. Herein, we demonstrate that 14-3-3{zeta} is necessary for lipolysis in male mice and fully differentiated 3T3-L1 adipocytes, as depletion of 14-3-3{zeta} significantly impaired glycerol and FFA release. Unexpectedly, this was not due to impairments in signaling events underlying lipolysis; instead, reducing 14-3-3{zeta} expression was found to significantly impact adipocyte maturity, as observed by reduced abundance of PPAR{gamma}2 protein and expression of mature adipocytes genes and those associated with de novo triglyceride synthesis and lipolysis. The impact of 14-3-3{zeta} depletion on adipocyte maturity was further examined with untargeted lipidomics, which revealed that reductions in 14-3-3{zeta} abundance promoted the acquisition of a lipidomic signature that resembled undifferentiated, pre-adipocytes. Collectively, these findings reveal a novel aspect of 14-3-3{zeta} in adipocytes, as reducing 14-3-3{zeta} was found to have a negative effect on adipocyte maturity and adipocyte-specific processes like lipolysis.