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

Activation of {beta}3-adrenergic receptors on mouse adipocytes promotes lipolysis, or the catabolism of stored lipids, via the concerted actions of PKA and lipases, including HSL, ATGL, and MAGL. Phosphorylation of HSL by PKA generates phospho-binding sites for 14-3-3 proteins, a ubiquitously expressed family of molecular scaffolds, of which we previously identified essential roles of the 14-3-3{zeta} isoform in murine adipogenesis. The presence of 14-3-3{zeta} binding sites on HSL and ATGL suggests that 14-3-3{zeta} may influence their activities and ultimately lipolysis. Herein, we demonstrate that 14-3-3{zeta} is necessary for lipolysis in male mice, as deletion of 14-3-3{zeta} in adipocytes was found to impair glycerol and FFA release. 14-3-3{zeta} was found to be heterogeneously expressed among adipocytes in gonadal white adipose tissue (gWAT), and deletion of 14-3-3{zeta} significantly decreased the number of small (<200m) adipocytes. Adipocyte-specific deletion of 14-3-3{zeta} also reduced PPAR{gamma} and HSL protein abundance and significantly reduced the expression of genes associated with adipocyte maturity. Similarly, depletion of 14-3-3{zeta} in mature 3T3-L1 adipocytes impaired lipolysis, and as with primary mouse adipocytes, reducing 14-3-3{zeta} abundance decreased the expression of mature adipocyte genes. Moreover, depletion of 14-3-3{zeta} promoted the acquisition of a lipidomic signature that resembled undifferentiated, immature 3T3-L1 cells. Collectively, these findings reveal a novel role for 14-3-3{zeta} in regulating PKA-dependent lipolysis, potentially by controlling the adipocyte maturity.