Recent Advances in Understanding the Role of IKKβ in Cardiometabolic Diseases.

Rebecca Hernandez,Changcheng Zhou

doi:10.3389/fcvm.2021.752337

Abstract

Cardiometabolic diseases, including cardiovascular disease, obesity, and diabetes, are the leading cause of mortality and morbidity worldwide. Cardiometabolic diseases are associated with many overlapping metabolic syndromes such as hypertension, hyperlipidemia, insulin resistance, and central adiposity. However, the underlying causes of cardiometabolic diseases and associated syndromes remain poorly understood. Within the past couple of decades, considerable progresses have been made to understand the role of inflammatory signaling in the pathogenesis of cardiometabolic diseases. The transcription factor, NF-κB, a master regulator of the innate and adaptive immune responses, is highly active in cardiometabolic diseases. IκB kinase β (IKKβ), the predominant catalytic subunit of the IKK complex, is required for canonical activation of NF-κB, and has been implicated as the critical molecular link between inflammation and cardiometabolic diseases. Recent studies have revealed that IKKβ has diverse and unexpected roles in mediating adiposity, insulin sensitivity, glucose homeostasis, vascular function, and atherogenesis through complex mechanisms. IKKβ has been demonstrated as a critical player in the development of cardiometabolic diseases and is implicated as a promising therapeutic target. This review summarizes current knowledge of the functions of IKKβ in mediating the development and progression of cardiometabolic diseases.

Highlights

Cardiometabolic diseases such as atherosclerosis, obesity, and diabetes are related to several risk factors termed cardiometabolic syndromes [1, 2]
For the purpose of this review, we focus on IKKβ, its known substrates, and their functions in the development of cardiometabolic diseases (Figure 1)
Previous studies demonstrated that constitutively active hepatic IKKβ induced obesity-independent systemic insulin resistance, while inhibiting hepatic NF-κB reversed both local and systemic insulin resistance [51, 76]. These findings indicate an important role of IKKβ in regulating hepatic and systemic insulin resistance

Summary

INTRODUCTION

Cardiometabolic diseases such as atherosclerosis, obesity, and diabetes are related to several risk factors termed cardiometabolic syndromes [1, 2]. IKKβ and its serine-threonine kinase activity are essential for regulating inflammatory and immune responses, and many studies have uncovered its function in chronic inflammation-associated cardiometabolic diseases such as atherosclerosis, obesity, and insulin resistance (Figure 1). Studies have found that IKKβ deficiency in adipocyte precursors or adipose lineage cells can protect mice from diet-induced obesity, systemic inflammation and insulin resistance [39, 54]. Deletion of adipocyte IKKβ did not affect obesity in mice but resulted in elevated adipose tissue inflammation, increased macrophage infiltration and exacerbate insulin resistance [59, 60] Skeletal muscle is another insulin responsive tissue that is impaired in obesity and diabetes [67]. Expression of cytokines/chemokines/protein levels (MCP-1, TNFα, IL-1β, IL-6, VCAM-1, ICAM-1)

Reduced NF-κB-mediated liver inflammation

Decreased body weight and systemic inflammation

Increased AGRP firing

Findings

CONCLUSION