Amyloid-B Induces Hepatic Insulin Resistance In Vivo via JAK2

摘要

Amyloid-β (AP), a natural product of cell metabolism, plays a key role in the pathogenesis of Alzheimer's disease (AD). Epidemio-logical studies indicate patients with AD have an increased risk of developing type 2 diabetes mellitus (T2DM). Ap can induce insulin resistance in cultured hepatocytes by activating the JAK2/ STAT3/SOCS-1 signaling pathway. Amyloid precursor protein and presenilin 1 double-transgenic AD mouse models with increased circulating Aβ level show impaired glucose/insulin tolerance and hepatic insulin resistance. However, whether Aβ induces hepatic insulin resistance in vivo is still unclear. Here we show C57BL/6J mice intraperitoneally injected with Ap42 exhibit increased fasting blood glucose level, impaired insulin tolerance, and hepatic insulin signaling. Moreover, the APPswe/PSENldE9 AD model mice intraperitoneally injected with anti-AP neutralizing antibodies show decreased fasting blood glucose level and improved insulin sensitivity. Injection of Ap42 activates hepatic JAK2/ STAT3/SOCS-1 signaling, and neutralization of Aβ in APPswe/ PSENldE9 mice inhibits liver JAK2/STAT3/SOCS-1 signaling. Furthermore, knockdown of hepatic JAK2 by tail vein injection of adenovirus inhibits JAK2/STAT3/SOCS-1 signaling and improves glucose/insulin tolerance and hepatic insulin sensitivity in APPswe/PSENldE9 mice. Our results demonstrate that Aβ induces hepatic insulin resistance in vivo via JAK2, suggesting that inhibition of Aβ signaling is a new strategy toward resolving insulin resistance and T2DM.