High-Fat-High-Fructose Diet Elicits Brown Adipocyte Dysfunction through miRNA-103 Induced miRNA Biogenesis Pathway

Abstract

Background: Obesity is a critical public health concern with its prevalence growing at an alarming rate worldwide. The Western diet that typically includes high-fat or high-fructose components is one of the leading contributing factors of obesity. Recent findings demonstrate the essential role of BAT in regulating whole-body metabolism. However, the explicit mechanism through which BAT maintains homeostasis is still unknown. Methods: Six-week-old C57BL/6 male mice were fed either a low-fat diet (LFD) or a high-fat high-fructose diet (HFHFD) for 4, 12, and 20 weeks. Results: We observed a significant increase in BAT weight under HFHFD along with BAT whitening in a time-dependent manner. This was also accompanied by a significant decrease in UCP1 and PGC1α protein, as well as a significant increase in the Bax/Bcl-2 ratio as early as 12 weeks, indicating increased apoptosis under HFHFD. Interestingly, miRNA-103 expression that holds a seed sequence within the miRNA biogenesis machinery, Dicer, was significantly upregulated after 12 and 20 weeks of HFHFD. Dicer and another biogenesis regulator, TRBP2, exhibited significant upregulation at 4 weeks of HFHFD. Conversely, those gene expressions were significantly downregulated at 12 and 20 weeks of HFHFD, followed by a significant decrease in the protein level at 12 weeks. To confirm the mechanistic connection, miRNA-103 knockdown in vitro significantly upregulated Dicer and the TRBP2 gene. However, only Dicer exhibited a significant increase at the translational level. Conclusion: Overall, we conclude that HFHFD may elicit BAT dysfunction by inhibiting Dicer via miRNA-103.

Keywords

• miRNAs
• miRNA biogenesis machinery
• brown adipose tissue
• high-fat high-fructose diet