The present review outlines possible mechanisms by which high fatty acids, associated with high-fat diet and obesity, impose insulin resistance on glucose uptake into skeletal muscle.
It is well established that muscle insulin resistance arises in conditions of high-fatty acid availability, and correlates with accumulation of triglycerides within skeletal muscle fibres. However, it is debated whether triglycerides or other lipid metabolites such as diacylglycerols and ceramides are directly responsible. These lipid metabolites can activate serine kinases that impair insulin signalling. Accumulation of acylcarnitines and reactive oxygen species could be additional causative agents of insulin resistance. Further, the precise defects in insulin signalling in muscle caused by high intramuscular lipid (i.e. lipotoxicity) remain unclear. In parallel, proinflammatory activation within the adipose tissue of obese and high-fat fed animals or humans causes muscle insulin resistance, and is ascribed to circulating inflammatory cytokines. Recent evidence also shows proinflammatory macrophages infiltrating muscle tissue and/or intermuscular adipose tissue, and there is growing evidence that fatty acids trigger macrophages to secrete factors that directly impair insulin actions. These factors are postulated to activate stress-signalling pathways in muscle that act on the same insulin-signalling components affected by lipotoxicity.
Altered intramuscular lipid metabolism, circulating cytokines, and inflammatory macrophage infiltration of muscle tissue have been recently linked to muscle insulin resistance provoked by fatty acids. Each is analysed separately in this review, but they may act simultaneously and synergistically to render skeletal muscle insulin-resistant.
Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
*Girish Kewalramani and Philip J. Bilan contributed equally to the writing of the article.
Correspondence to Amira Klip, PhD, Cell Biology Program, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada Tel: +1 416 813 6392; fax: +1 416 813 5028; e-mail: firstname.lastname@example.org