Adipocyte Membrane Cholesterol Regulates Obesity

OBJECTIVE: Adipose tissue cholesterol increases with adipocyte triglyceride (TG) content and size during development of obesity. However, how adipocyte cholesterol affects adipocyte function is poorly understood. The aim of this study was to evaluate the role of the cellular cholesterol exporter, ATP binding cassette transporter A1 (Abca1), on adipose tissue function during diet-induced obesity. APPROACH AND RESULTS: Adiponectin Cre recombinase transgenic mice were crossed with Abca1 (flox/flox) mice to generate adipocyte-specific Abca1 knockout (ASKO) mice. Control (Cntl) and ASKO mice were then fed a high fat, high cholesterol (45% calories as fat, 0.2% cholesterol) diet for 16 weeks. Compared to Cntl mice, ASKO mice had a 2-fold increase in adipocyte plasma membrane cholesterol content and significantly lower body weight, epididymal fat pad weight, and adipocyte size. ASKO vs. Cntl adipose tissue had decreased peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein expression, nuclear sterol regulatory element binding protein 1 (SREBP1) protein, lipogenesis, and TG accretion, but similar Akt activation after acute insulin stimulation. Acute siRNA-mediated Abca1 silencing during 3T3L1 adipocyte differentiation reduced adipocyte Abca1 and PPARγ protein expression and triglyceride content. Systemic stimulated TG lipolysis and glucose homeostasis was similar between Cntl and ASKO mice. CONCLUSIONS: Adipocyte Abca1 is a key regulator of adipocyte lipogenesis and lipid accretion, likely due to increased adipose tissue membrane cholesterol, resulting in decreased activation of lipogenic transcription factors PPARγ and SREBP1.