<i>Garcinia cambogia</i> attenuates adipogenesis by affecting CEBPB and SQSTM1/p62-mediated selective autophagic degradation of KLF3 through RPS6KA1 and STAT3 suppression

The overexpansion of adipose tissues leads to obesity and eventually results in metabolic disorders. <i>Garcinia cambogia</i> (<i>G. cambogia</i>) has been used as an antiobesity supplement. However, the molecular mechanisms underlying the effects of <i>G. cambogia</i> on cellular processes have yet to be fully understood. Here, we discovered that <i>G. cambogia</i> attenuated the expression of CEBPB (CCAAT/enhancer binding protein (C/EBP), beta), an important adipogenic factor, suppressing its transcription in differentiated cells. In addition, <i>G. cambogia</i> inhibited macroautophagic/autophagic flux by decreasing autophagy-related gene expression and autophagosome formation. Notably, <i>G. cambogia</i> markedly elevated the expression of KLF3 (Kruppel-like factor 3 (basic)), a negative regulator of adipogenesis, by reducing SQSTM1/p62-mediated selective autophagic degradation. Furthermore, increased KLF3 induced by <i>G. cambogia</i> interacted with CTBP2 (C-terminal binding protein 2) to form a transcriptional repressor complex and inhibited <i>Cebpa</i> and <i>Pparg</i> transcription. Importantly, we found that RPS6KA1 and STAT3 were involved in the <i>G. cambogia</i>-mediated regulation of CEBPB and autophagic flux. In an obese animal model, <i>G. cambogia</i> reduced high-fat diet (HFD)-induced obesity by suppressing epididymal and inguinal subcutaneous white adipose tissue mass and adipocyte size, which were attributed to the regulation of targets that had been consistently identified <i>in vitro</i>. These findings provide new insight into the mechanism of <i>G. cambogia</i>-mediated regulation of adipogenesis and suggest molecular links to therapeutic targets for the treatment of obesity. <b>Abbreviations:</b> 3-MA: 3-methyladenine; ACTB: actin beta; ATG: autophagy-related; Baf: bafilomycin A₁; BECN1: beclin 1; CEBP: CCAAT/enhancer binding protein (C/EBP); CHX: cycloheximide; CREB: cAMP response element binding protein; CTBP: C-terminal binding protein; EGCG: (-)-epigallocatechin gallate; eWAT: epididymal white; <i>G. cambogia: Garcinia cambogia</i>; GFP: green fluorescent protein; H&amp;E: hematoxylin and eosin; HFD: high-fat diet; iWAT: inguinal subcutaneous white; KLF: Kruppel-like factor; LAP: liver-enriched transcriptional activating proteins; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; ND: normal diet; PPARG: peroxisome proliferator activated receptor gamma; qPCR: quantitative real-time PCR; RFP: red fluorescent protein; RPS6KA1: ribosomal protein S6 kinase A1; siRNA: small-interfering RNA; SQSTM1/p62: sequestosome 1; STAT: signal transducer and activator of transcription; TEM: transmission electron microscopy