Leflunomide Effective in Fighting Obesity by inducing lipophagy: Study

A recent study published in the FASEB Journal has uncovered a new pathway to combat obesity. Leflunomide, a medication typically used to treat rheumatoid arthritis, has shown unexpected potential in aiding weight loss and reducing blood glucose levels in patients.

Recent studies have shed light on the mystery, revealing that the active metabolite of leflunomide, known as A77 1726, plays a key role in activating a process called lipophagy. Lipophagy is a specific form of selective autophagy responsible for breaking down lipid droplets, and it is closely linked to obesity.

A77 1726 was found to induce LC3 lipidation, prompting an increase in autophagosomes and lipoautolysosomes, effectively leading to the breakdown of lipid droplets in adipocytes (fat cells). This process was activated through a complex signaling cascade involving TGF-β-activated kinase 1 (TAK1), AMP-activated kinase (AMPK), and Unc-51 like autophagy-activated kinase 1 (ULK1).

Notably, A77 1726 reduced the lipid content in fat cells, confirming its role in combating obesity at a cellular level. This effect was further validated when A77 1726-treated mice, particularly those with genetic obesity (ob/ob mice), experienced restricted weight gain, decreased visceral fat deposits, and smaller adipocytes.

Moreover, leflunomide treatment induced autophagy not only in adipose tissue but also in the liver, leading to reduced hepatic lipid content. This suggests that leflunomide's anti-obesity properties extend beyond fat cells.

The research also revealed a link to the protein S6K1, previously associated with insulin resistance. A deficiency in S6K1 was found to increase levels of LC3 lipidation in various tissues, reinforcing the connection between this protein and obesity.

These findings open exciting new avenues for the treatment and understanding of obesity, a global health epidemic. Leflunomide's ability to activate AMPK and induce lipophagy provides fresh insights into its anti-obesity mechanisms. 

Source:

Ji, X., Chen, J., You, C., Sun, J., & Xu, X. (2023). Leflunomide alleviates obesity via activation of the TAK1‐AMPK pathway and induction of lipophagy. In The FASEB Journal (Vol. 37, Issue 11). Wiley. https://doi.org/10.1096/fj.202301162r