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Achieving Inner Balance: How to Keep Metabolites on the Level

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Researchers led by a team from the University of Tsukuba find that a single protein regulates both sugar and fat metabolism in the liver


Tsukuba, Japan—Keeping everything running smoothly inside the human body is a tricky business that involves a multitude of checks and balances to make sure that an exquisite equilibrium is maintained. Now, researchers from Japan have identified a single protein that helps balance both sugar and fat levels in the liver and could be a promising drug target for treating symptoms associated with obesity.


In a study published this month in Nature Communications, researchers led by a team from the University of Tsukuba have revealed that C-terminal binding protein 2 (CtBP2) is a global regulator of metabolism that is crucial for balancing sugar and fat metabolism in the liver.


Metabolism is the process by which our bodies break down nutrients into smaller parts that can be used by individual cells to carry out their normal activities. The metabolism of different food components has to be balanced carefully to make sure that everything is maintained at optimal levels and keeps running smoothly; and this balance is maintained by a host of regulatory proteins.


"CtBP2 is a regulatory protein that senses changes in the relative levels of certain metabolites and responds by altering the expression of other proteins," explains lead author of the study Professor Motohiro Sekiya. "Our preliminary findings showed that CtBP2 may be specifically involved in glucose metabolism in the liver, so we wanted to investigate this possibility in more detail."


To do this, the researchers explored the genes, proteins, and metabolites that CtBP2 interacts with.


"The results were somewhat surprising," states Professor Sekiya, "as we found that CtBP2 interacted with multiple proteins to regulate the expression of genes related not only to glucose metabolism, but also to lipid metabolism and inflammation, all of which are involved metabolic disease."


In fact, the researchers found that CtBP2 levels are low in obese mice, as well as in liver samples from deceased obese individuals, which could explain the imbalances in sugar and fat metabolism seen with obesity. Conversely, giving obese mice extra CtBP2 improved their health by promoting a healthier metabolite balance, further demonstrating the pivotal role of this protein in maintaining optimum metabolism.


"Our findings suggest that CtBP2 is a master integrator of metabolic signals in the liver that is crucial for controlling glucose and lipid balance," says Professor Sekiya.


The team showed that a site on CtBP2 called the Rossmann fold was crucial for the protein to carry out these activities, so designing drugs to target this active site could be a new avenue toward treating people with metabolic disorders. Given that current treatments for diabetes address sugar metabolism at the expense of fat metabolism, possibly damaging liver health, a single drug that could target both of these functions could also be an important step forward for diabetics.


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This study was supported by a fellowship from the Manpei Suzuki Diabetes Foundation (to Motohiro Sekiya), the Advanced Research and Development Programs for Medical Innovation (PRIME) of the Japan Agency for Medical Research and Development (AMED; grant number JP18gm5910007), the Japan Society for the Promotion of Science, the Takeda Science Foundation, the Suzuken Memorial Foundation, the Ono Medical Research Foundation, the MSD Life Science Foundation and the Novartis Foundation for the Promotion of Science. The research was partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (BINDS) from AMED (grant number JP19am0101094).



Original Paper

The article, "The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis ," was published in Nature Communications at DOI: 10.1038/s41467-021-26638-5


Correspondence

Associate Professor SEKIYA Motohiro
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba


Related Link

Faculty of Medicine