Impact of different ectopic fat depots on cardiovascular and metabolic diseases

Abstract

A growing body of evidence is pointing out the pathophysiological role of fat accumulation in different organs. Ectopic fat depots within heart, liver, skeletal muscle, kidney, and pancreas as well as around blood vessels might be more associated to cardiometabolic risk than classical variables, such as body mass index.Among different mechanisms, lipid metabolism appears to be particularly influenced by ectopic fat depots. Indeed, intracellular accumulation of nonesterified fatty acids, and triglycerides promotes endoplasmic reticulum stress, mitochondrial uncoupling, oxidative stress, and altered membrane composition/function, finally promoting inflammatory response and cell death. The dysfunctional adipose tissue was shown to induce both local and systemic effects, with relevant clinical consequences. Epicardial fat and myocardial steatosis have been associated with the development of atrial fibrillation and ventricular dysfunction. Similarly perivascular adipose tissue appears to trigger atherosclerosis and hypertension. Nonalcoholic fatty liver disease has been recognized both as the hepatic manifestation of metabolic syndrome and as a cardiovascular (CV) risk factor. Importantly, the renal sinus fat emerged as a potential player in kidney dysfunction. Finally, both skeletal muscle and pancreatic fat depots have been indicated as potential endocrine modulators of insulin resistance.Considering the global rise in the prevalence of obesity, the understanding of mechanisms underlying ectopic fat accumulation represents an urgent need, with potential clinical implications for CV risk stratification. Here, we attempt to update the current knowledge of the different ectopic fat depots, focusing on underlying mechanisms and potential clinical implications.

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

“…In the kidney, ectopic lipid deposition contributes to the local inflammation and oxidative stress [30,68]. In DN patients, dyslipidemia promotes ectopic lipid accumulation and lipid intermediates (e.g., palmitate, ceramides, and saturated NEFA), not only in kidney but also in extra-renal tissues such as liver, pancreas, and heart [4,49,69].…”

“…Cytoplasmatic lipid droplets accumulation influences the progression of inflammation and fibrosis in several genetic and metabolic pathologies [79]. These lipid mediators have been associated with the activation of the inflammatory response, ROS production, mitochondrial dysfunction, autophagy deregulation, endoplasmic reticulum stress (ER stress) and apoptosis [69,80,81]. This fact is mainly due to the accumulation of intermediary toxic metabolites, such as diacylglycerol, fatty acyl-CoA, ceramides, and sphingolipids, which are involved in protein kinase C (PKC) activation, triglyceride synthesis, and mitochondrial dysfunction [82,83].…”

Macrophages in the pathophysiology of NAFLD: The role of sex differences

“…The close link with dysfunctional visceral adipose tissue has been extensively investigated. Adipocyte hypertrophy, hypoxia and inflammatory cell recruitment all contribute to insulin resistance and limited lipid storage capacity 41 . A huge amount of FFAs and pro‐inflammatory cytokines is then released into the portal vein, directly to the liver.…”

Excessive “orthotopic” fat accumulation: Links with cardiometabolic diseases and potential drug treatment

“…Excessive "orthotopic" fat accumulation: Links with cardiometabolic diseases and potential drug treatment To the Editor, Ferrara, Montecucco, Dallegri, and Carbone (2019) reviewed the effects of adipose tissue accumulation in different organs on oxidative stress, inflammation, insulin resistance, and atherosclerosis.…”

“…The excessive accumulation of adipose tissue, and possibly dysfunctional transformation, may lead to the secretion of proatherogenic and proinflammatory factors (Aldiss et al, 2017). Ferrara et al (2019) also mention the potential benefit of statins, sodium-glucose cotransporter 2 inhibitors (SGLT2i), and glucagonlike peptide-1 receptor agonists (GLP-1 RAs) in patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). In this context, there is some evidence that statins can reduce cardiovascular risk and improve both biochemical and histological features of NAFLD/NASH; although, appropriately designed trials are necessary (Athyros et al, 2017).…”