Abstract
Skeletal muscle mitochondrial dysfunction, evidenced by incomplete beta oxidation and accumulation of fatty acid intermediates in the form of long and medium chain acylcarnitines, may contribute to ectopic lipid deposition and insulin resistance during high fat diet (HFD)-induced obesity. The present review discusses the roles of anterograde and retrograde communication in nucleo-mitochondrial crosstalk that determines skeletal muscle mitochondrial adaptations, specifically alterations in mitochondrial number and function in relation to obesity and insulin resistance. Special emphasis is placed on the effects of high fat diet (HFD) feeding on expression of nuclear-encoded mitochondrial genes (NEMGs) nuclear receptor factor 1 (NRF-1) and 2 (NRF-2) and peroxisome proliferator receptor gamma coactivator 1 alpha (PGC-1α) in the onset and progression of insulin resistance during obesity and how HFD-induced alterations in NEMG expression affect skeletal muscle mitochondrial adaptations in relation to beta oxidation of fatty acids. Finally, the potential ability of acylcarnitines or fatty acid intermediates resulting from mitochondrial beta oxidation to act as retrograde signals in nucleo-mitochondrial crosstalk is reviewed and discussed.
Highlights
Obesity and type 2 diabetes (T2D) represent a major healthcare issue
Fatty acid oxidation (FAO) and the activity of enzymes involved in mitochondrial fatty acid transport and oxidation, such as carnitine palmitoyltransferase 1 (CPT-1) and citrate synthase (CS), are lower in the skeletal muscle during obesity, and higher intramyocellular lipid (IMCL) content is observed in insulin resistant subjects [18,19]
Because studies investigating the effects of dietary fat composition are lacking, this study focuses on the effects of dietary fat content and discuss the formation, transport, and localization of acylcarnitines, and the role of acylcarnitines in high fat diet (HFD)-induced obesity and T2D
Summary
Recent data suggest that about 35% of the adult US population is considered obese [1], whereas 9.3% of the population, i.e., 29.1 million people, have diabetes [2] Unhealthy lifestyle choices such as low physical activity, excess caloric intake, and consumption of high fat diets (HFD) contribute to metabolic disorders such as obesity, T2D, diabetic dyslipidemia, and non-alcoholic fatty liver disease [3,4,5]. Fatty acid oxidation (FAO) and the activity of enzymes involved in mitochondrial fatty acid transport and oxidation, such as carnitine palmitoyltransferase 1 (CPT-1) and citrate synthase (CS), are lower in the skeletal muscle during obesity, and higher intramyocellular lipid (IMCL) content is observed in insulin resistant subjects [18,19]. We discuss the role of NEMGs in regulating mitochondrial adaptations in the skeletal muscle in relation to HFD-induced obesity and insulin resistance
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