Lipotoxicity: the obese and endurance-trained paradox

• Published in: International Journal of Obesity Vol. 28; no. S4; pp. S66 - S71
• Main Author: Russell, A.P
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2004
• Subjects: Adipose tissues; Animals; Exercise - physiology; fatty acids; gene expression; Genetic aspects; Health aspects; homeostasis; Humans; insulin; Insulin resistance; Insulin Resistance - physiology; Kinases; Lipids; lipotoxicity; Models, Biological; Muscle, Skeletal - metabolism; Myocardium - metabolism; Obesity; Obesity - metabolism; Obesity - physiopathology; oxidation; Oxidation-Reduction; patients; Peroxidation; phosphorylation; Physical Endurance - physiology; protein kinase C; Protein Kinase C - metabolism; proteins; Risk factors; signal transduction; Signal Transduction - physiology; skeletal muscle; triacylglycerols; Triglycerides; Triglycerides - analysis; Triglycerides - metabolism; tumor necrosis factor-alpha; tyrosine; Switzerland
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/sj.ijo.0802859

The potential lipotoxic effect of intramyocellular triglyceride (IMTG) accumulation has been suggested to be a major component in the development of insulin resistance. Increased levels of IMTGs correlate with insulin resistance in both obese and diabetic patients, but this relationship does not exist in endurance trained (ETr) subjects. This may be, in part, related to differences in the gene expression and activities of key enzymes involved in fatty acid transport and oxidation as well as in the perodixation status of the IMTGs in obese/diabetic patients as compared with ETr subjects. Disruptions in fat and lipid homeostasis in skeletal muscle have been shown to activate protein kinase C (PKC), which acts on several downstream signalling pathways, including the insulin and the I(kappa)B kinase (IKK)/NF(kappa)B signalling pathways. Additionally, an increased peroxidation of IMTGs may reduce insulin sensitivity by increasing TNFα, which is known to increase the expression of suppressor of cytokine signalling proteins (SOCS). A common characteristic observed when activating both PKC and TNFα/SOCS3 is the inhibition of tyrosine phosphorylation of IRS-1 and subsequently an inhibition of its activation of downstream signalling molecules. These may be important players in the development of insulin resistance and understanding their activation and expression in both obese and ETr humans should assist in understanding how and why IMTGs become lipotoxic.