The Beijing Genome found that Entakacan was able to bind directly to FTO and inhibit its m6A demethylating enzyme activity.

Obesity-related genes (FATTo) are the first genes found to play an important role in obesity and play an important role in regulating weight and fat content, but it has long been unclear whether specific molecular mechanisms and the ability to use small molecular compounds to inhibit FTO activity to treat obesity-related metabolic diseases have long been unclear.
, Yang Yungui of the Beijing Genomics Research Institute of the Chinese Academy of Sciences and a team of Huang Andzhang, beijing Institute of Life Sciences, found that Entakapen, an FDA-approved Parkinson's-assisted treatment drug, was able to regulate metabolic energy by inhibiting The m6A (N6-Methyladenosine) demethylase activity of FTO.
research published online April 17 in the journal Science Translational Medicine under the title Ofacapone as a chemical of opto mediating the published through FOXO1.
m6A modification as the most abundant modification type on messenger RNA, and is widely involved in life processes such as mammalian development, immunity, stem cell renewal, fat differentiation, and tumor generation and metastasis. Using structure-based virtual screening methods, the
team found that Entakapine was able to bind directly to FTO and inhibit its m6A demethylase activity, withno inhibition of another m6A demethylating enzyme ALKBH5 and DNA methylation and histone modification.
study found that mice exhibited significant weight loss, significantly lower blood sugar levels, and significantly increased concentration of adipose tissue after taking enthakapen.
then found that G6PC, the key gene for glycogenesis, showed significant lying down after FTO knocked down.
by analyzing the transcription group of liver tissue and the modification spectrum data of m6A in mice with liver FTO conditional knockout, it was found that the level of two m6A modified sites on FOXO1 messenger RNA in The FTO condition knockout was increased, thus regulating G6PC expression.
To further study how FTO regulates the expression of G6PC in mouse livers, the researchers observed fluorescence imaging in mice by integrating the G6PC promoter luciferase reporting system with adenoviruses.
liver conditional knockout of FTO or FOXO1, as well as mice fed entapaeapen, showed signs of decreased G6PC signaling.
wild FTO can refill G6PC fluorescence signals and M6A demethylating key amino acid mutations of FTO can not be successfully refilled, confirming the FTO-FOXO1-G6PC pathway in the liver to regulate blood glucose change mechanism.
researchers also found that the molecular mechanism of enthacarboon's increasein heat production in the mice's groin white adipose tissue (iWAT) was also due to the reduction of the foxO1 protein expression due to the increase in m6A levels on FOXO1 messenger RNA after The FTO was inhibited.
different from liver tissue, FOXO1 inhibition of transcription factors in adipose tissue can increase the expression of UCP1, the key factor in heat production.
the UCP1 promoter's luciferenzyme report genetic experiments confirmed that the fTO knocklow m6A modification level rose in FOXO1 messenger RNA, causing FOXO1 protein expression to decline, thus increasing the expression of UCP1.
the study further reveals the molecular mechanisms of FTO regulation in energy metabolism, and the discovery of FTO inhibitor enthakapen has some guiding significance for clinical use in obese patients.
the research was supported by the Chinese Academy of Sciences' strategic leading science and technology project, the national key research and development program and the National Natural Science Foundation of China.
Source: Beijing Genomics Research Institute.