Metabolic Signaling in the Sakamoto Group

The Sakamoto Group investigates key molecular signaling mechanisms that control energy metabolism and glucose homeostasis associated with exercise, insulin resistance and type 2 diabetes.

Research focus

Every human cell is governed by highly complex networks of signaling molecules that work together to regulate cellular functions and maintain organismal homeostasis. Majority of the key metabolic enzymes are specifically and coordinately regulated through interplay between allosteric and covalent post-translational modification (e.g. phosphorylation) regulations in response to changes in the levels of various factors, including hormones/cytokines, nutrients, and metabolites. Elucidating the molecular control and physiological role of such interplay is critical to understand complex metabolic processes and for discovery of potential new therapies.

A major strength of the group is that we established a robust and unique approach, consisting of structure-guided mutagenesis, detailed enzyme kinetics of the mutant proteins, and comprehensive in vivo metabolic analyses. This has enabled us for example to reveal the key role that an allosteric activator of glucose metabolite (glucose 6-phosphate) plays in regulating insulin-stimulated glycogen synthesis in vivo in skeletal muscle and liver.

Main findings

“Discovery of key molecular insights into the mechanism of the action of first-line anti-diabetes drug metformin”
This work was published in Nature Medicine in 2018 (PMID: 30150719). Metformin is a first-line drug for the treatment of individuals with type 2 diabetes. Despite the clinical success of metformin over 50 years, there is no clear consensus as to its mode of action and multiple, seemingly contradictory mechanisms, have been proposed. In this study, we have identified a key molecular mechanism by which metformin suppresses hepatic glucose production through AMP-dependent inhibition of fructose-1-6-bisphosphatase.

“Identification of the LKB1-salt-inducible kinase pathway as key regulatory axis in control of hepatic gluconeogenesis”
This work was published in Nature Communication in 2014 (PMID: 30150719). LKB1, originally identified as tumor suppressor, has recently been established as a master kinase that regulates metabolism and growth through the energy-sensing AMP-activated protein kinase (AMPK) and 12 other closely related kinases, including salt-inducible kinases (SIKs). In this study, we have demonstrated that the SIKs function as key gluconeogenic gate-keepers downstream of LKB1 through regulation of transcriptional co-activators and the gluconeogenic program in the liver. 

“Identification of the mechanism of action of small-molecule activators of the master metabolic regulator AMP-activated protein kinase (AMPK)”
AMPK is a sensor of cellular energy status and a promising target for drugs aimed at metabolic disorders. There are several AMPK activators identified. We identified key and unique mechanism of action of the first direct activator termed A-769662 (PMID: 17855357), C13 (PMID: 25036776, PMID: 26952388) and ancient natural drug salicylate (PMID: 22517326).

Staff of the Sakamoto Group

Group leader: Professor Kei Sakamoto