Treatment with exendin-4 at concentrations seen in either treated diabetic patients33 or at levels of GLP-1 seen in postbariatric surgery patients34, 35 results in decreased hepatic TG content. These data clearly

underscore that GLP-1 has a direct, independent, and novel action on steatotic hepatocytes. Our Barasertib purchase study also provides a molecular mechanism to explain the signal effectors of GLP-1 in its potential role in hepatocyte TG reduction. A key signaling effector for insulin signaling downstream from IRS-1 is AKT. Based on our data, we have outlined a proposed molecular pathway whereby GLP-1 or homologs intersect the insulin signaling pathway in hepatocytes (Fig. 6), because this and interrelated pathways in hepatocytes have emerged as critical for the molecular basis of the emergence of hepatocyte insulin resistance. It has been widely reported that AKT phosphorylation selleck inhibitor is markedly diminished in steatotic hepatocytes.36 In this study, we show that GLP-1 ligands increase not only the phosphorylation status of AKT but other key molecules downstream. Our signaling studies are noteworthy because they confirm that exendin-4 not only activated AKT, but also resulted

in robust phosphorylation of both PDK-1 and PKC-ζ. However, we failed to knock down AKT phosphorylation by siGLP-1R, although we were successful in doing so against PKD-1 and PKC-ζ. These data provide a plausible mechanism by which exendin-4 may bypass AKT activation in patients with hepatic insulin resistance. PDK-1 activates PKC-ζ; moreover,

PKC-ζ appears to have a significant role in exendin-4–mediated lypolysis in rat adipocytes. Studies by Arnes et al.37 in the rat liver showed that GLP-1 significantly increased Glut 2 messenger RNA levels, increasing lipolysis. In addition, knockout ifenprodil studies of IRS-1 and IRS-2 in rat hepatocytes by Sajan et al.38 demonstrated that both appear to activate the AKT pathway, but that only IRS-2 appears to activate the PKC-ζ. Our data suggest that GLP-1R activates the same pathway as IRS-2, which may account for our failure to knock down AKT phosphorylation and our ability to significantly knock down PDK-1 and PKC-ζ phosphorylation. What is apparent from our data is that more than one pathway related to insulin signal transduction can act to execute an action of insulin, but in this case such an action (reduction in TG store in liver cells) was executed by GLP-1 proteins. The siRNA studies knocking out GLP-1R demonstrate a novel insulin action of GLP-1 proteins by up-regulating key elements of the hepatocyte insulin signaling pathway (Fig. 6). Future cellular analysis should focus on GLP-1 proteins which serve as insulin sensitizing agents in hepatocytes as opposed to an incretin effect seen in pancreatic β cells.