(n3) Fatty Acids Alleviate Adipose Tissue Inflammation and Insulin Resistance: Mechanistic Insight

Obesity is associated with the metabolic syndrome, a significant risk factor for developing type 2 diabetes and cardiovascular diseases. Chronic low grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metabolic syndrome. Although the exact trigger of this inflammatory process is unknown, adipose tissue hypoxia, endoplasmic reticular stress, and saturated fatty acid mediated activation of innate immune processes have been identified as important processes in these disorders. Furthermore, macrophages and T lymphocytes have important roles in orchestrating this immune process. Although energy restriction leading to weight loss is the primary dietary intervention to reverse these obesity-associated metabolic disorders, other interventions targeted at alleviating adipose tissue inflammation have not been explored in detail. In this regard, (n3) PUFA of marine origin both prevent and reverse high fat diet induced adipose tissue inflammation and insulin resistance in rodents. We provide an update on the pathogenesis of adipose tissue inflammation and insulin resistance in obesity and discuss potential mechanisms by which (n3) PUFA prevent and reverse these changes and the implications in human health. (Authors abstract)
Obesity is a major health problem in the United States and worldwide. It is associated with metabolic syndrome, which is characterized by hyperglycemia, abdominal obesity, hypertension, elevated plasma TG, and reduced plasma HDL cholesterol levels. Individuals with metabolic syndrome frequently exhibit proinflammatory and prothrombotic metabolic profiles and are at a higher risk for developing type 2 diabetes and cardiovascular disease. Recent evidence has causally linked obesity and increased adiposity to the pathogenesis of metabolic syndrome and type 2 diabetes. Furthermore, adipose tissue dysfunction and inflammation have been identified as major players in these disorders.  (n3) PUFA, namely EPA and DHA, have antiinflammatory properties, reduce plasma TG and exhibit antiobesity effects on humans and rodents. This review provides an update on the mechanistic aspects of the pathogenesis of adipose tissue inflammation and insulin resistance in obesity, followed by a summary of potential mechanisms by which EPA and DHA prevent and reverse these processes. Obesity and increased adiposity are associated with a chronic, low grade inflammation in the adipose tissue. Current evidence suggests that adipose tissue hypoxia, immune cell chemotaxis to adipose tissue followed by subsequent activation, ER stress, and SFA mediated activation of innate immune receptors play a role in the trigger of this inflammatory process. ATM and T lymphocytes are the 2 key immune cell types that orchestrate these processes. Adipose tissue inflammation and associated hepatic steatosis is causally linked to the development of skeletal muscle and systemic insulin resistance. EPA and DHA prevent excessive adiposity and insulin resistance in rodents. Mechanistically, this is related to the ability of these fatty acids to increase hepatic, skeletal muscle, and adipose tissue fatty acid oxidation and their ability to reduce lipogenesis. EPA and DHA also have important antiinflammatory properties that modulate adipose tissue inflammation via GPR120 mediated suppression of macrophage proinflammatory cytokine secretion, resolvin, and protectin-mediated resolution of inflammation. Through modulation of adipokine secretion, these fatty acids also favor insulin sensitivity. Further studies in obese humans are warranted to study whether these fatty acids can prevent and reverse the progression of metabolic syndrome to type 2 diabetes. (Editors comments)