Hepatic glucose production mediated by omega-3 fatty acids: the role of Galphaq/11 protein

Abstract

Diabetes mellitus has reached epidemic proportions in recent decades and constitutes one of the greatest challenges of today's health systems. Type 2 diabetes mellitus (DM2) results from insulin resistance, a phenomenon closely associated with chronic and low grade inflammation, characteristic of obesity. The obesogenic process leads to a myriad of metabolic disorders, which significantly impairs glucose homeostasis in the organism. When the liver becomes resistant to insulin, glycogen synthesis is impaired while the gluconeogenic pathway remains active; this results in a constant hyperglycemic state in the individual. In order to treat this pathophysiological condition anti-inflammatory nutritional strategies have been widely studied; these include the use of omega-3 and omega-9 unsaturated fatty acids. These fatty acids act by signaling through the GPR120/²-arrestin-2/TAB1,2,3 protein complex to disrupt pro-inflammatory cascades such as TNF-± and TLR-4 (toll-like receptor 4) to thereby impact positively on the insulin signaling pathway. However, there are published reports suggesting that in addition to signaling via the GPR120/²-arrestin-2/TAB1,2,3 complex, GPR120 might also signal via the G proteins, G±q and G±11 to trigger signaling mechanisms that improve glycemic control. Specifically, it was demonstrated through in vitro studies that upon as the activation of GPR120 by É-3 fatty acids, the G±q/11 subunits associate with the p110 catalytic subunit of PI3-K (phosphatidylinositol-3-kinase) thereby activating this protein kinase. PI3-K then phosphorylates and activates another kinase, Akt, which propagates the É-3 fatty acid signals to the cell nucleus resulting in the phosphorylation of the transcriptional factor FoxO-1. FoxO-1 then modulates the transcription of genes which encode proteins such as PEPCK, G-6Pase and GS, that are involved in glucose metabolism, Based on these in vitro findings we hypothesize that in vivo É-3 fatty acids exert their positive effects on glucose metabolism via the GPR120/G±q/11 signaling complex and that the genetic deletion of G±q/11 in the mouse liver is sufficient to inhibit the beneficial effects of these nutrients on glucose homeostasis, in the context of obesity and diabetes. (AU)