The plant hormone, 6-benzylaminopurine, ameliorates obesity in male and female mice while on a high-fat diet

Obesity is a global health crisis. Currently available treatments, while effective, show several undesirable side effects that hinder their long-term use. Herein, we investigated the anti-obesity potential of 6-benzylaminopurine (BAP), a plant hormone commonly used in agricultural settings to enhance plant development, in obese mice and mammalian cell models. Orally administered BAP induced significant weight loss in diet induced obese male and female CD-1 mice through sex-specific mechanisms involving appetite suppression, adipose tissue remodeling, and enhanced lipid utilization. Concurrently, BAP improves several metabolic parameters associated with obesity, including glucose tolerance, fasting blood glucose, hyperleptinemia, hyperinsulinemia, white adipose tissue browning, and liver health. In murine- and human-hypothalamic neuronal models, BAP suppresses the expression of feeding stimulating neuropeptide Y (Npy) and increases the anorexigenic pro-opiomelanecortin (Pomc). Using RNA-sequencing, we identified that BAP inhibits EGFR/ErbB2 and MEK/ERK/EGR1 signaling, whereas MEK/ERK inhibition is partially responsible for the in vitro effects of BAP, including Npy downregulation. Moreover, similar MEK/ERK inhibition was also shown to be involved in the induction of thermogenic markers, including uncoupling protein 1 (Ucp1), in 3T3-L1 derived adipocyte, indicating a consistent molecular mechanism of BAP across different cell types. Overall, our data showed that BAP could serve as an efficacious and alternative treatment avenue for obesity with a unique mechanism of action compared to currently available options.