Expression and Role of β3-Adrenergic Receptor during the Differentiation of 3T3-L1 Preadipocytes into Adipocytes

SIMPLE SUMMARY: The β3-adrenergic receptor (β3-AR) has long been viewed as a potential therapeutic target for dealing with obesity. Although the lipolytic and thermogenic role of β3-AR in brown/beige adipocytes is well defined, the β3-AR’s adipogenic role in white adipocytes remains unclear at present. In this study, we investigated the expression and function of β3-AR in 3T3-L1 murine white preadipocytes. Knockdown of β3-AR led to less lipid accumulation and triglyceride (TG) content as well as less expression and phosphorylation levels of CCAAT/enhancer-binding protein-α (C/EBP-α) and peroxisome proliferator-activated receptor-γ (PPAR-γ) during 3T3-L1 preadipocyte differentiation. These findings reveal that the β3-AR inhibitor or antagonist could be a promising candidate for potential preventive and therapeutics against obesity. ABSTRACT: β3-adrenergic receptor (β3-AR) is expressed predominantly in mature white and brown/beige adipocytes. Although the lipolytic and thermogenic role of β3-AR in brown/beige adipocytes is well defined, the adipogenic role of β3-AR in white adipocytes remains unclear at present. In this study, we investigated the expression and function of β3-AR in differentiating 3T3-L1 cells, murine white preadipocytes. Of note, the expression of β3-AR at the protein and mRNA levels was highly induced in a time-dependent manner during 3T3-L1 preadipocyte differentiation. Interestingly, the results of the pharmacological inhibition study demonstrated the roles of p38 MAPK and PKC in the induction of β3-AR expression in differentiating 3T3-L1 cells. Knockdown of β3-AR led to less lipid accumulation and triglyceride (TG) content during 3T3-L1 preadipocyte differentiation with no cytotoxicity. Furthermore, knockdown of β3-AR resulted in a decrease in not only expression levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FASN), perilipin A, and leptin but also phosphorylation levels of signal transducer and activator of transcription-5 (STAT-5) during 3T3-L1 preadipocyte differentiation. In summary, these results demonstrate firstly that β3-AR expression is highly up-regulated in p38 MAPK and PKC-dependent manners, and the up-regulated β3-AR plays a crucial role in lipid accumulation in differentiating 3T3-L1 cells, which is mediated through control of expression and phosphorylation levels of C/EBP-α, PPAR-γ, STAT-5, FASN, and perilipin A.