This study investigated the effects and molecular mechanism of a combination of capsaicin and capsiate on promoting lipid metabolism and inducing browning in 3T3-L1 white adipocytes. The combination significantly suppressed lipid accumulation in adipocytes ( p = 0.019) and robustly improved lipid metabolic profiles, including decreased triacylglycerol (0.6703 ± 0.0385 versus 0.2849 ± 0.0188 mmol/g of protein; p < 0.001), total cholesterol (0.1282 ± 0.0241 versus 0.0651 ± 0.0178 mmol/g of protein; p = 0.003), and low-density lipoprotein cholesterol (0.0021 ± 0.0017 versus 0.0005 ± 0.0002 mmol/g of protein; p = 0.024) and increased high-density lipoprotein cholesterol (0.0162 ± 0.0141 versus 0.1002 ± 0.0167 mmol/g of protein; p = 0.012). Furthermore, this combination markedly upgraded the protein levels of cluster of differentiation 36 ( p = 0.007) and adipose triglyceride lipase ( p = 0.013) and phosphorylation of hormone-sensitive lipase at Ser660, Ser565, and Ser563 ( p < 0.001, p = 0.027, and p = 0.002, respectively), indicating increases of fatty acid transport and lipolysis. The levels of lipid metabolism regulators, phosphorylation of adenosine-monophosphate-activated protein kinases α and β ( p = 0.011, and p < 0.001, respectively), sirtuin 1 ( p = 0.004), and vanilloid transient receptor subtype I ( p = 0.014) were also increased by the combination. Moreover, the combination greatly activated the browning program in adipocytes, as demonstrated by increases in beige-specific gene and protein. Further research found that the protein levels of peroxisome proliferator-activated receptor γ (PPARγ; p = 0.001) and β₃-adrenergic receptor (β₃-AR; p = 0.026) were elevated by the combination, and most of the beige-specific markers were abolished by pretreatment of antagonists of PPARγ or β₃-AR. In conclusion, these results indicated that a combination of capsaicin and capsiate could induce browning in white adipocytes via activation of the PPARγ/β₃-AR signaling pathway, and this combination might be worth investigating as a potential cure for obesity.

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