Targeting GSK-3β for adipose dysfunction and cardiovascular complications of metabolic disease: An entangled WNT/β-catenin question

Abstract

Individuals with metabolic syndrome have a high risk of developing cardiovascular disorders that is closely tied to visceral adipose tissue dysfunction, as well as an altered interaction between adipose tissue and the cardiovascular system. In metabolic syndrome, adipose tissue dysfunction is associated with increased hypertrophy, reduced vascularization, and hypoxia of adipocytes, leading to a pro-oxidative and pro-inflammatory environment. Among the pathways regulating adipose tissue homeostasis is the wingless-type mammary tumor virus integration site family (Wnt) signaling pathway, with both its canonical and non-canonical arms. Various modulators of the Wnt signaling have been identified to contribute to the development of metabolic diseases and their cardiovascular complications, with a particularly significant role played by Glycogen Synthase Kinase-3β (GSK-3β). GSK-3β levels and activities have various and often contrasting roles in obesity and related metabolic disorders, as well as their cardiovascular sequelae. Here, we explore the possibility that altered Wnt signaling and GSK-3β activities could serve as a connection between adipose tissue dysfunction and the development of cardiovascular disease in individuals with metabolic syndrome. We attempt to define a context-specific approach for intervention, which could possibly serve as a novel disease modifying therapy for the mitigation of such complications.

Keywords: Wnt/β‐catenin signaling; adipogenesis; adipose tissue; glycogen synthase kinase‐3β; hyperplasia; hypertrophy.