Endurance exercise training increases APPL1 expression and improves insulin signaling in the hepatic tissue of diet‐induced obese mice, independently of weight loss

Abstract

Hepatic insulin resistance is the major contributor to fasting hyperglycemia in type 2 diabetes. The protein kinase Akt plays a central role in the suppression of gluconeogenesis involving forkhead box O1 (Foxo1) and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), and in the control of glycogen synthesis involving the glycogen synthase kinase beta (GSK3β) in the liver. It has been demonstrated that endosomal adaptor protein APPL1 interacts with Akt and blocks the association of Akt with its endogenous inhibitor, tribbles-related protein 3 (TRB3), improving the action of insulin in the liver. Here, we demonstrated that chronic exercise increased the basal levels and insulin-induced Akt serine phosphorylation in the liver of diet-induced obese mice. Endurance training was able to increase APPL1 expression and the interaction between APPL1 and Akt. Conversely, training reduced both TRB3 expression and TRB3 and Akt association. The positive effects of exercise on insulin action are reinforced by our findings that showed that trained mice presented an increase in Foxo1 phosphorylation and Foxo1/PGC-1α association, which was accompanied by a reduction in gluconeogenic gene expressions (PEPCK and G6Pase). Finally, exercised animals demonstrated increased at basal and insulin-induced GSK3β phosphorylation levels and glycogen content at 24 h after the last session of exercise. Our findings demonstrate that exercise increases insulin action, at least in part, through the enhancement of APPL1 and the reduction of TRB3 expression in the liver of obese mice, independently of weight loss.

A Novel Mechanism for Vascular Insulin Resistance in Normotensive Young SHRs

“…23 Moreover, chronic exercise increases APPL1 expression, which mediates exercise-induced increase of insulin action in the liver of diet-induced obese mice. 24 The results from the present study showed that in adiponectin-deficient mice, downregulation of APPL1 expression impaired insulin-induced vasodilatation, whereas augmented insulin-induced vasoconstriction. In addition, adiponectin treatment partly restored APPL1 expression, and thus reversed the imbalance between insulin-induced signaling in ySHRs and APN −/− mice.…”

Nonfunctional overreaching and hepatic adaptations of APPL1 and APPL2

“…APPL1 downregulation is associated with GSK3beta phosphorylation decreased in liver of obese mice under fasting conditions. However, in response to endurance exercise training, these obese mice increased APPL1 expression, Akt/ APPL1 association, and GSK-3beta phosphorylation 23 , which corroborates our consideration above.…”

“…It is known that APPL1 can limit the interaction between Akt and TRB3 in mouse liver tissue, which is accompanied by an increase in the membrane translocation of APPL1, Akt activation, and enhancement in response to insulin stimulation 22,23 . Also, adiponectin also stimulates APPL1 in mouse hepatocyte cells with activation of another class of proteins, the p38 mitogen-activated protein kinases (p38MAPK), which activates glucose transporters protein.…”

APPL1 transgenic mice are protected from high-fat diet-induced cardiac dysfunction

“…This observation could be expected based on related literature (8,12,36,42) demonstrating insulin sensitizing actions of APPL1 in liver and skeletal muscle. Indeed, APPL1 levels were significantly decreased in endothelium of Zucker diabetic fatty rats (38), and a recent study suggested that chronic exercise in mice increased hepatic APPL1 expression, which, at least in part, accounted for improved insulin sensitivity (28). However, in a human study, there was higher APPL1 expression in type 2 diabetic muscle, and weight loss in these individuals was associated with reduced skeletal muscle APPL1 level (22).…”