Mammalian 5′-AMP-activated protein kinase (AMPK) is a key nutrient sensor for maintaining cellular energy status and a known therapeutic target for glucose control in type 2 diabetes (T2D) . Despite current understandings of its well-established roles in regulating glucose metabolism in various tissues, AMPK functions in the intestine, the first-line organ for nutrient processing, remains largely elusive. We have uncovered a novel link between intestinal AMPK activation and brown adipose tissue (BAT) thermogenic regulation through modulating the anti-microbial peptide (AMP) -controlled gut microbiota and their metabolites. Therefore, the intestinal AMPK-AMP-microbiota-BAT axis is a potential target for the treatment of T2D. Berberine, a quaternary ammonium protoberberine alkaloid with an isoquinoline scaffold isolated from medicinal herbs, has been used to treat T2D in animal models as well as human trials, while offsetting renal, cardiovascular, hepatic, and respiratory risks. However, its poor bioavailability severely limits its application and development. As such, there is a dire need to explore structural modifications of berberine to obtain better pharmacological properties and elucidate its underlying mechanisms of action. Berberine can activate AMPK indirectly by inhibition of mitochondrial respiration in the adipocyte, myotubes and liver; however, its effects on intestinal AMPK are still unknown. We have successfully synthesized natural and non-natural novel berberine derivatives. We will determine their antidiabetes effects and elucidate the underlying mechanisms of action in targeting the intestinal AMPK-AMP pathways for T2D treatment. Moreover, our study will provide a better structure-activity relationship to guide the future design of berberine derivatives with higher potency and improved bioavailability.
E.Zhang: None.
