Tipepidine activates AMPK and improves adipose tissue fibrosis and glucose intolerance in high‐fat diet‐induced obese mice

Abstract

AbstractTipepidine (3‐[di‐2‐thienylmethylene]‐1‐methylpiperidine) (TP) is a non‐narcotic antitussive used in Japan. Recently, the potential application of TP in the treatment of neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder, has been suggested; however, its functions in energy metabolism are unknown. Here, we demonstrate that TP exhibits a metabolism‐improving action. The administration of TP reduced high‐fat diet‐induced body weight gain in mice and lipid accumulation in the liver and increased the weight of epididymal white adipose tissue (eWAT) in diet‐induced obese (DIO) mice. Furthermore, TP inhibited obesity‐induced fibrosis in the eWAT. We also found that TP induced AMP‐activated protein kinase (AMPK) activation in the eWAT of DIO mice and 3T3‐L1 cells. TP‐induced AMPK activation was abrogated by the transfection of liver kinase B1 siRNA in 3T3‐L1 cells. The metabolic effects of TP were almost equivalent to those of metformin, an AMPK activator that is used as a first‐line antidiabetic drug. In summary, TP is a potent AMPK activator, suggesting its novel role as an antidiabetic drug owing to its antifibrotic effect on adipose tissues.