Inflammation in obesity is the common link between defects in fatty acid metabolism and insulin resistance.
Over the past two decades increases in obesity, due to high caloric intakes and immobilizing technologies, has led to a surge in type 2 diabetes. In obesity elevated circulating fatty acids set-off a pro-inflammatory cascade that increases the production of tumour necrosis factor-alpha(TNFalpha) from macrophages. Obesity is associated with blunted skeletal muscle fatty acid oxidation, accumulation of bioactive lipids and insulin resistance. The factors contributing to defects in fatty acid metabolism are not understood but new data demonstrates that increased TNFalpha in obesity increases protein phosphatase 2C (PP2C), which in turn suppresses the activity of AMP-activated protein kinase (AMPK), a critical regulator of energy metabolism.(1) These data identify a novel mechanism by which inflammation in obesity is a precursor to defects in skeletal muscle fatty acid oxidation that generates a vicious cycle exacerbating the development of insulin resistance.
Steinberg
Gregory R
GR
St. Vincent's Institute, Fitzroy, Victoria, Australia. gsteinberg@svi.edu.au
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D005227:Fatty Acids / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology*; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000737:chemistry; D009765:Obesity / Q000150:complications*; D010084:Oxidation-Reduction; D010749:Phosphoprotein Phosphatases / Q000378:metabolism / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
D005227:Fatty Acids; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C000607456:PPM1A protein, human; C000607457:PPM1B protein, human; C000607460:PPM1G protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C