Obesity-induced metabolic imbalance allosterically modulates CtBP2 to inhibit PPAR-alpha transcriptional activity.

Maintenance of metabolic homeostasis is secured by metabolite-sensing systems, which can be overwhelmed by constant macronutrient surplus in obesity. Not only the uptake processes but also the consumption of energy substrates determine the cellular metabolic burden. We herein describe a novel transcriptional system in this context comprised of peroxisome proliferator-activated receptor alpha (PPARα), a master regulator for fatty acid oxidation, and C-terminal binding protein 2 (CtBP2), a metabolite-sensing transcriptional corepressor. CtBP2 interacts with PPARα to repress its activity, and the interaction is enhanced upon binding to malonyl-CoA, a metabolic intermediate increased in tissues in obesity and reported to suppress fatty acid oxidation through inhibition of carnitine palmitoyltransferase 1. In line with our preceding observations that CtBP2 adopts a monomeric configuration upon binding to acyl-CoAs, we determined that mutations in CtBP2 that shift the conformational equilibrium toward monomers increase the interaction between CtBP2 and PPARα. In contrast, metabolic manipulations that reduce malonyl-CoA decreased the formation of the CtBP2-PPARα complex. Consistent with these in vitro findings, we found that the CtBP2-PPARα interaction is accelerated in obese livers while genetic deletion of CtBP2 in the liver causes derepression of PPARα target genes. These findings support our model where CtBP2 exists primarily as a monomer in the metabolic milieu of obesity to repress PPARα, representing a liability in metabolic diseases that can be exploited to develop therapeutic approaches.

C-Terminal Binding Protein 2 Emerges as a Critical Player Linking Metabolic Imbalance to the Pathogenesis of Obesity.

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.

Loss of CtBP2 may be a mechanistic link between metabolic derangements and progressive impairment of pancreatic ß cell function.

The adaptive increase in insulin secretion in early stages of obesity serves as a safeguard mechanism to maintain glucose homeostasis that cannot be sustained, and the eventual decompensation of ß cells is a key event in the pathogenesis of diabetes. Here we describe a crucial system orchestrated by a transcriptional cofactor CtBP2. In cultured ß cells, insulin gene expression is coactivated by CtBP2. Global genomic mapping of CtBP2 binding sites identifies a key interaction between CtBP2 and NEUROD1 through which CtBP2 decompacts chromatin in the insulin gene promoter. CtBP2 expression is diminished in pancreatic islets in multiple mouse models of obesity, as well as human obesity. Pancreatic ß cell-specific CtBP2-deficient mice manifest glucose intolerance with impaired insulin secretion. Our transcriptome analysis highlights an essential role of CtBP2 in the maintenance of ß cell integrity. This system provides clues to the molecular basis in obesity and may be targetable to develop therapeutic approaches.