LNK deficiency decreases obesity-induced insulin resistance by regulating GLUT4 through the PI3K-Akt-AS160 pathway in adipose tissue

Abstract

In recent years, LNK, an adapter protein, has been found to be associated with metabolic diseases, including hypertension and diabetes. We found that the expression of LNK in human adipose tissue was positively correlated with serum glucose and insulin in obese people. We examined the role of LNK in insulin resistance and systemic energy metabolism using LNK-deficient mice ( LNK -/- ). With consumption of a high-fat diet, wild type (WT) mice accumulated more intrahepatic triglyceride, higher serum triglyceride (TG), free fatty acid (FFA) and high sensitivity C-reactive protein (hsCRP) compared with LNK -/- mice. However, there was no significant difference between LNK -/- and WT mice under normal chow diet. Meanwhile, glucose transporter 4 (GLUT4) expression in adipose tissue and insulin-stimulated glucose uptake in adipocytes were increased in LNK -/- mice. LNK -/- adipose tissue showed activated reactivity for IRS1/PI3K/Akt/AS160 signaling, and administration of a PI3K inhibitor impaired glucose uptake. In conclusion, LNK plays a pivotal role in adipose glucose transport by regulating insulin-mediated IRS1/PI3K/Akt/AS160 signaling.

LNK promotes granulosa cell apoptosis in PCOS via negatively regulating insulin-stimulated AKT-FOXO3 pathway

“…In the current study, we found that GLUT4 mRNA level was elevated in LNK knockout PCOS mice. The mechanism of LNK-altered GLUT4 expression was further explored in our other work, in which similar results were found in HFD-induced insulin resistant mice [ 30 ].…”

“…The ethics committee for animal research in Sun Yat-sen University approved the experiments and we followed the NIH Guide for the Care and Use of Laboratory Animals [ 30 ]. Mice were kept under standard conditions (12 hours light/dark, with free access to feed and water).…”

“…Whole body LNK -knockout (KO) C57BL/6 mice were designed by Can-ZhaoLiu, and were produced with CRISPR/Cas by Cyagen Biosciences Inc, as described in our previous study [ 30 ]. The animals were divided into four groups.…”

“…Meanwhile, mice were fed a high-fat diet (PCOS group, 60% fat calories) or regular chow (control group, 10% fat calories). The high-fat diet was also used in our previous study [ 30 ].…”

“…In ITT, after fasting for 6 hours, intraperitoneal 0.75 units/kg body weight insulin (Sigma) injection was performed. Glucose levels were detected from tail venous blood with an automated glucometer (Roche) at 0 min, 15 min, 30 min, 60 min, 90 min, 120 min after injection, which was also described in our previous study [ 30 ].…”