Fat-Specific Knockout of Mecp2 Upregulates Slpi to Reduce Obesity by Enhancing Browning.

Abstract

Abnormalities of methyl-CpG binding protein 2 (Mecp2) cause neurological disorders with metabolic dysfunction; however, its role in adipose tissues remains unclear. Here, we report upregulated Mecp2 in white adipose tissues (WAT) of obese humans, as well as in obese mice and during in vitro adipogenesis. Normal chow-fed adipocyte-specific Mecp2 knockout mice (<i>Mecp2</i> ^<i>Adi</i> KO mice) showed a lean phenotype, with downregulated lipogenic genes and upregulated thermogenic genes that were identified using RNA sequencing. Consistently, the deficiency of Mecp2 in adipocytes protected mice from high-fat diet (HFD)-induced obesity and inhibited in vitro adipogenesis. Furthermore, <i>Mecp2</i> ^<i>Adi</i> KO mice showed increased browning under different stimuli, including cold treatment. Mechanistically, Mecp2 bound to the promoter of secretory leukocyte protease inhibitor (<i>Slpi</i>) and negatively regulated its expression. Knockdown of <i>Slpi</i> in inguinal WAT of <i>Mecp2</i> ^<i>Adi</i> KO mice prevented cold-induced browning. Moreover, recombinant SLPI treatment reduced the HFD-induced obesity via enhancing browning. Together, our results suggest a novel non-central nervous system function of Mecp2 in obesity by suppressing browning, at least partially, through regulating adipokine Slpi.