Emerging Role of Adipocyte Dysfunction in Inducing Heart Failure Among Obese Patients With Prediabetes and Known Diabetes Mellitus

Abstract

Adipose tissue dysfunction is a predictor for cardiovascular (CV) events and heart failure (HF) in patient population with obesity, metabolic syndrome, and known type 2 diabetes mellitus. Previous preclinical and clinical studies have yielded controversial findings regarding the role of accumulation of adipose tissue various types in CV risk and HF-related clinical outcomes in obese patients. There is evidence for direct impact of infiltration of epicardial adipocytes into the underlying myocardium to induce adverse cardiac remodeling and mediate HF development and atrial fibrillation. Additionally, perivascular adipocytes accumulation is responsible for release of proinflammatory adipocytokines (adiponectin, leptin, resistin), stimulation of oxidative stress, macrophage phenotype switching, and worsening vascular reparation, which all lead to microvascular inflammation, endothelial dysfunction, atherosclerosis acceleration, and finally to increase in CV mortality. However, systemic effects of white and brown adipose tissue can be different, and adipogenesis including browning of adipose tissue and deficiency of anti-inflammatory adipocytokines (visfatin, omentin, zinc-α2-glycoprotein, glypican-4) was frequently associated with adipose triglyceride lipase augmentation, altered glucose homeostasis, resistance to insulin of skeletal muscles, increased cardiomyocyte apoptosis, lowered survival, and weak function of progenitor endothelial cells, which could significantly influence on HF development, as well as end-organ fibrosis and multiple comorbidities. The exact underlying mechanisms for these effects are not fully understood, while they are essential to help develop improved treatment strategies. The aim of the review is to summarize the evidence showing that adipocyte dysfunction may induce the onset of HF and support advance of HF through different biological mechanisms involving inflammation, pericardial, and perivascular adipose tissue accumulation, adverse and electrical cardiac remodeling, and skeletal muscle dysfunction. The unbalancing effects of natriuretic peptides, neprilysin, and components of renin-angiotensin system, as exacerbating cause of altered adipocytokine signaling on myocardium and vasculature, in obesity patients at high risk of HF are disputed. The profile of proinflammatory and anti-inflammatory adipocytokines as promising biomarker for HF risk stratification is discussed in the review.

Keywords: adipose tissue; biomarkers; cardiac and vascular remodeling; co-morbidities; heart failure.

Figure 1

The interplay between metabolic derangements and heart failure development. BAT, brown adipose tissue; BP, blood pressure; ET, endothelin-1; HFpEF, heart failure with preserved ejection fraction; HFmrEF, heart failure with midrange ejection fraction; HFrEF, heart failure with reduced ejection fraction; NPs, natriuretic peptides; RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic nervous system; PPAR-γ, peroxisome proliferator-activated receptor coactivator-1γ; WAT, white adipose tissue.

Figure 2

The role of insulin and AMPK in growth, differentiation, and survival of cells. AMPK, 5′-AMP–activated protein kinase; IRK, insulin receptor kinase; PI3K, phosphatidylinositol 3-kinase; CAP–CBL–TC10, the Cb1-associated protein (CAP)–casitas B-lineage lymphoma (CBL)–ras-like protein TC10; PKC, protein kinase C; JNK-1, c-Jun N-terminal kinase 1; SIK2, salt-inducible kinase 2.

Figure 3

Interrelation between several phenotypes of macrophages, dendritic cells, and adipose tissue. The proportion of M2 macrophages is higher in BAT than in WAT and consequently lower mass of BAT in patients with AO, and type 2 DM is associated with weak anti-inflammatory ability of non–adipose tissue cells including M2 macrophages and regulatory T cells. As a result of the modification of immune phenotypes of adipose tissue macrophages and increase in WAT in patients with diabetes and patients with metabolically active obesity, the effect of M1 macrophages begins to prevail. It leads to microvascular inflammation, accelerating atherosclerosis, endothelial dysfunction, insulin resistance, skeletal muscle dysfunction, and finally cardiac and vascular remodeling and HF. TNF, tumor necrosis factor; IL, interleukin; TGF, transforming growth factor; ABCA1, ATP-binding cassette subfamily A member 1; PLIN2, perilipin-2; PD-L1, programmed cell death 1 ligand; CX3CL1, fractalkine.

Figure 4

The role of free fatty acids–related stimulation of p53 and local production of adipocytokines in pathogenesis of HF. TLR4, toll-like receptor-4; NF-κB, nuclear factor κβ; TNF-α, tumor necrosis factor α; WAT, white adipose tissue; BAT, brown adipose tissue; IL, interleukin; RBP4, retinol-binding protein-4; ANGPTL2, angiopoietin-related protein 2.