Novel Perspective for Understanding the Pathogenesis of Metabolic Diseases Focusing on a Metabolite Sensor

Abstract

Historically, attempts to understand the pathogenesis of obesity have focused on hormonal perspectives, as exemplified by insulin. However, concurrent upregulation of hepatic gluconeogenesis and lipogenesis, one of the specific aspects of obesity-related pathogenesis, cannot be explained simply by insulin resistance, implying gaps in existing knowledge. C-terminal binding protein 2 (CtBP2) is a metabolite sensor that can be activated by NADH. We have demonstrated that CtBP2 is inactivated upon interaction with fatty acyl-CoAs, which are increased in tissues in obesity, thereby playing a critical role in this pathogenetic process. In the liver, CtBP2 suppresses gluconeogenesis and lipogenesis in healthy subjects but is dysregulated in obesity, leading to diabetes and steatosis. Inactivation of CtBP2 also contributes to the progressive decline of pancreatic β-cell function in obesity, suggesting possible involvement of CtBP2 in a variety of tissues. This article discusses the pathogenesis of obesity from metabolic perspectives by focusing on CtBP2.