Metabolic Signaling in the Sakamoto Group

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

Group photo of the Sakamoto Group
From left to right: Dipsikha Biswas, Greg Robert Markby, Ionela Florentina Negoita, Fiona Louise Roberts, Katarzyna Maria Luda, Kei Sakamoto, Marianne Agerholm Jensen, Anna Kristina Hellberg, Tenna Holgersen Bryde, Danial Ahwazi

 

 

 

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.

 

 

 

 

 

 

“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: 25088745). 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).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Group Leader

Kei Sakamoto
Professor

Phone +45 35 33 40 07
kei.sakamoto@sund.ku.dk

Twitter: @kei_sakamoto

Linkedin: Kei Sakamoto at CBMR

Kei Sakamoto

Staff list

Name Title Phone E-mail
Addinsall, Alex Bernard Postdoc +4535333560 E-mail
Ahwazi, Danial PhD Student +4535325398 E-mail
Biswas, Dipsikha Postdoc +4535333454 E-mail
Choi, Beatrice So-Yun Postdoc +4535327121 E-mail
Fraguas Bringas, Conchita PhD Fellow +4535321343 E-mail
Hellberg, Anna Kristina Staff Scientist +4520894788 E-mail
Holgersen Bryde, Tenna PhD Fellow +4581616072 E-mail
Jensen, Marianne Agerholm Staff Scientist +4535325063 E-mail
Lopez Escalera, Silvia Andrea Visiting PhD Student   E-mail
Luda, Katarzyna Maria Postdoc   E-mail
Negoita, Ionela Florentina Postdoc   E-mail
Pradas Juni, Marta Staff Scientist +4535324485 E-mail
Sakamoto, Kei Professor +4535334007 E-mail