Adaptation and maladaptation of the heart in obesity

Abstract

Obesity affects the cardiovascular system at many different levels, including the heart muscle itself. Clinical and experimental studies have shown an accumulation of triglycerides and other lipid species in cardiomyocytes. Analogous to hepatic steatosis, investigators have introduced the term “cardiac steatosis”. The present review addresses the complex relationships between cardiac fuel homeostasis, insulin resistance, and proposed mechanisms of damage to cardiomyocytes in different models of obesity, insulin resistance, and lipotoxicity. Specifically, the review weighs the evidence whether there is a heart muscle disorder in human obesity. It discusses how adipokines can modulate cardiac metabolism, and it focuses on the metabolic remodeling accompanying increased fatty acid supply in the heart of rodent models of lipotoxicity, with special attention to the role played by mitochondrial uncoupling and futile cycling. We stress the notion that, in spite of the many proposed mechanisms, cardiac lipotoxicity is still a hypothesis rather than an established pathophysiologic principle. Although the concept of a “lipotoxic cardiomyopathy” seems attractive, we propose instead a series of steps on a path from adaptation to maladaptation of the heart in obesity. A case in point is insulin resistance of the heart which may be both adaptive (protecting the heart from excess fuel) or maladaptive (associated with reactive oxygen species formation and activation of signaling pathways of programmed cell death). The present literature reflects an extraordinary complexity of the heart’s metabolic, functional and structural changes in obesity.

Figure 1. The Transcriptional Control of Oxidative Metabolism by the Nuclear Receptors

The transcription of distinct cassettes of genes of fatty acid utilization or oxidation are mediated by nuclear receptors (e.g. PPAR and ERR) which require coactivators or corepressors to confer the specificity of response to distinct fatty acid challenges.

Figure 2. Putative Role of the Decrease in Fatty Acid-Responsive Genes in the Development of Contractile Dysfunction with Western Diet Compared to High Fat Diet Feeding

Fatty acid (FA) enters the cell through fatty acid transporters and diffusion, fatty acid transport protein (FATP) and or fatty acid translocase (CD36), and is activated to fatty acyl-CoA (FA-CoA) by an isoform of acyl-CoA synthetase (ACS). The activated Fatty acyl-CoA can undergo hydrolysis (at the indirect expense of ATP) via cytosolic thioesterase 1 (CTE1), which is decreased in the western diet compared to the high fat diet thus decreasing the capacity for fatty acid-mediated futile cycling. After entry of Fatty Acyl-CoAs into the mitochondrion via carnitine palmitoyltransferase (CPT) and carnitine-acylcarnitine translocase (CACT), mitochondrial thioesterase 1 (MTE1) and uncoupling protein 3 (UCP3), or adenine nucleotide translocase (ANT), have the capacity to “uncouple” fat oxidation (indicated with dashed lines), which may result in a increased free CoASH pool for complete β-oxidation and decreased production of reactive oxygen species (ROS) by the electron transport chain. Therefore fatty acyl-CoAs may not accumulate and are not shuttled into “lipotoxic pathways.” Adapted from Wilson et al.