High-fat diet feeding and palmitic acid increase CRC growth in β2AR-dependent manner

Epidemiology studies indicate that consumption of high-fat diet (HFD) is directly associated with the development of colorectal cancer (CRC). However, the exact component in HFD and the mechanism underlying its effect on CRC growth remained unclear. Our study shows that HFD feeding increases beta 2AR expression in the xenograft tissues of CRC-bearing mouse model; the elevated beta 2AR expression is reduced when HFD is replaced by control diet, which strongly suggests an association between HFD feeding and beta 2AR expression in CRC. HFD feeding increases palmitic acid and stearic acid levels in CRC; however, only palmitic acid increases beta 2AR expression, which is dependent upon Sp1. beta 2AR plays the dominant role in promoting CRC cell proliferation among all the beta-AR subtypes. More importantly, knockout of beta 2AR or knockdown of Sp1 abolishes the palmitic acid increased CRC cell proliferation, suggesting palmitic acid increases CRC cell proliferation in beta 2AR-dependent manner. HFD or palmitic acid-rich diet (PAD) also fails to increase the tumor growth in xenograft mouse models bearing beta 2AR-knockout CRC cells. beta 2AR promotes CRC growth by increasing the phosphorylation of HSL at the residue S552. The phosphorylated and activated HSL (S552) changes the metabolic phenotype of CRC and increases energy production, which promotes CRC growth. Our study has revealed the unique tumorigenic properties of palmitic acid in promoting CRC growth, and have delineated the underlying mechanism of action. We are also the first to report the linkage between HFD feeding and beta-adrenergic signaling pathway in relation to CRC growth.