Exercise counteracts lipotoxicity by improving lipid turnover and lipid droplet quality

Abstract

This is an article from the symposium 14th Key Symposium -Metabolic Complications of Obesity.Abstract. Zacharewicz E, Hesselink MKC, Schrauwen P (Maastricht University Medical Center, Maastricht). Exercise counteracts lipotoxicity by improving lipid turnover and lipid droplet quality (Key Symposium). J Intern Med 2018; https://doi. org/10.1111/joim.12729The incidence of obesity and metabolic disease, such as type 2 diabetes mellitus (T2D), is rising globally. Dietary lipid over supply leads to lipid accumulation at ectopic sites, such as skeletal muscle. Ectopic lipid storage is highly correlated with insulin resistance and T2D, likely due to a loss of metabolic flexibility -the capacity to switch between fat and glucose oxidation upon insulin stimulation -and cellular dysfunction because of lipotoxicity. However, muscle lipid levels are also elevated in endurance-trained athletes, presenting a paradoxical phenotype of increased intramuscular lipids along with high insulin sensitivity -the 'athletes' paradox'. This review focuses on recent human data to characterize intramuscular lipid species in order to elucidate some of the underlying mechanisms driving skeletal muscle lipotoxicity. There is evidence that lipotoxicity is characterized by an increase in bioactive lipid species, such as ceramide. The athletes' paradox supports the notion that regular physical exercise has health benefits that might originate from the alleviation of lipotoxicity. Indeed, exercise training alleviates intramuscular ceramide content in obese individuals without a necessary decrease in ectopic lipid storage. Furthermore, evidence shows that exercise training elevates markers of lipid droplet dynamics such as the PLIN proteins, and triglyceride lipases ATGL and HSL, as well as mitochondrial efficiency, potentially explaining the improved lipid turnover and a reduction in the accumulation of lipotoxic intermediates observed with the athelets' paradox.

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

“…Regular exercise is one of the fundamental pillars for bodyweight reduction and decrease local and systemic inflammatory microenvironment [247][248][249]. Increasing energy demand by skeletal muscle contraction promotes glucose homeostasis by peripheral lipolysis and liver NEFA oxidation [250][251][252]. In addition to bodyweight reduction (with its anti-proteinuric effect), the improvement of metabolic kidney milieu and endothelial function restoration could also account for the renoprotective effects of regular exercise on diabetic chronic disease [253][254][255].…”

Lipotoxicity plays a key role in the development of both insulin resistance and muscle atrophy in patients with type 2 diabetes

“…Trained athletes are also characterized by elevated fat content in the muscle, but in contrast to their sedentary counterparts, they are highly insulin sensitive . The precise mechanism by which trained persons are protected from the insulin desensitizing effects of IMCL is still incompletely understood, but here is substantial evidence that exercise enhances the regulation of lipid droplet degradation and synthesis and increases oxidative capacity, resulting in lower levels of detrimental lipid intermediates . Furthermore, exercise leads to improved insulin sensitivity in adipose tissue, possibly resulting in lower levels of uncontrolled fatty acid release, and thus less fatty acid spillover to skeletal muscle and liver .…”

“…[134][135][136][137] The precise mechanism by which trained persons are protected from the insulin desensitizing effects of IMCL is still incompletely understood, but here is substantial evidence that exercise enhances the regulation of lipid droplet degradation and synthesis and increases oxidative capacity, resulting in lower levels of detrimental lipid intermediates. 138,139 Furthermore, exercise leads to improved insulin sensitivity in adipose tissue, possibly resulting in lower levels of uncontrolled fatty acid release, 140 and thus less fatty acid spillover to skeletal muscle and liver. 141 Considering this, it is no wonder that exercise is fundamental in the treatment of diabetes.…”

Could Omega 3 Fatty Acids Preserve Muscle Health in Rheumatoid Arthritis?

“…Muscle lipotoxicity 50µM EPA or DHA TG, DG and ceramides content [9] Endurance training lipid turnover and improve lipid droplets quality [135] EPA muscle regeneration capacity of C 2 C 12 muscle cells exposed to palmitate [68] Muscle mass and function Omega 3 during 8 weeks protein anabolic response in healthy adults [129] Acute resistance exercise preserved lean body mass, muscle anabolic response and muscle function [136,137] Omega 3 supplementation muscle protein rate and phosphorylation of mTOR Ser2448 and p70S6K Thr389 [128] Long term training program combining strength and endurance muscle functions [138] DHA muscle protein degradation in C 2 C 12 [125,126] CV diseases 2g omega 3 (46% EPA-38% DHA) endothelial function and arterial stiffness [112] Exercise is associated with a reduced vascular stiffness in RA [139] 3 months anti-TNF-α treatment improved blood pressure in RA patients [133] Omega 3 endothelial function in 16 patients with hypertriglyceridemia [105] Resistance exercise improves endothelial function in type 2 diabetes subjects [140] 3 months anti-TNF-α treatment improved endothelial function in RA patients [141] Omega 3 fatty acids FMD [111] Moderated-vigourous physical activity FMD and blood pressure and not affected vascular function [142] TNF-α inhibitors the incidence of CV diseases [86] Nutrition could have protective effect against perturbations in lipid profile, muscle lipotoxicity, sarcopenia and CV diseases that occur in RA patients. Indeed, an omega 3 supplementation improve lipid profile by increasing HDL-c plasma levels and decreasing TC and LDL-c levels.…”