Journal of atherosclerosis and thrombosisOct 4, 2023

The Role of C-Terminal Binding Protein 2 in Connecting Metabolic Imbalance to the Development of Obesity

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Feb 27, 2026

Abstract

C-terminal binding protein 2 (CtBP2) plays a critical role in sensing metabolites related to metabolic homeostasis.

CtBP2 binds preferentially to NADH over NAD, linking its activation to glycolysis.
Increased glycolysis leads to higher levels of NADH, activating CtBP2 and supporting metabolic functions.
Fatty acyl-CoAs, which accumulate during obesity, can inactivate CtBP2.
CtBP2 monitors both redox state and energy substrate preference, contributing to metabolic balance.
In healthy individuals, CtBP2 activation helps protect against metabolic disturbances.
Inactivation of CtBP2 in obesity is associated with the development of metabolic issues.

Simplified

Metabolism is one of the vital functions of cells and living organisms, and the systems to sense and respond to the metabolic alterations play pivotal roles in a plethora of biological processes, including cell proliferative activities, immune cell functions, aging processes, and neuronal functions. Recently, we have reported that a transcriptional cofactor, C-terminal binding protein 2 (CtBP2), serves as a critical metabolite sensor in this context. CtBP2 has a structural pocket called Rossmann fold to accommodate metabolites, and it has been reported to be activated upon binding to NADH/NAD. Owing to its preferential binding affinity for NADH compared with NAD, increased glycolysis activates CtBP2 by regenerating NADH from NAD. Furthermore, we recently reported that fatty acyl-CoAs, metabolites accumulated under the condition of lipid overload, as represented by obesity, can inactivate CtBP2. These observations suggest that CtBP2 monitors not only redox state but also energy substrate preference in the maintenance of metabolic homeostasis. In line with these metabolite-sensing capabilities, CtBP2 is activated in healthy subjects to protect against metabolic disturbances, whereas inactivation of CtBP2 in obesity contributes to the pathogeneses of obesity.This metabolic system orchestrated by CtBP2 can provide a novel framework for understanding how cells maintain their homeostasis through coordination of metabolism, and CtBP2 incapacitation can be a critical point of the obesogenic cascade. ＋＋＋

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The Role of C-Terminal Binding Protein 2 in Connecting Metabolic Imbalance to the Development of Obesity

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