Amyloid-? induces hepatic insulin resistance in vivo via JAK2.

ABSTRACT: Amyloid-? (A?), a natural product of cell metabolism, plays a key role in the pathogenesis of Alzheimer's disease (AD). Epidemiological studies indicate patients with AD have an increased risk of developing type 2 diabetes mellitus (T2DM). A? 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 A? level show impaired glucose/insulin tolerance and hepatic insulin resistance. However, whether A? induces hepatic insulin resistance in vivo is still unclear. Here we show C57BL/6J mice intraperitoneally injected with A?42 exhibit increased fasting blood glucose level, impaired insulin tolerance, and hepatic insulin signaling. Moreover, the APPswe/PSEN1dE9 AD model mice intraperitoneally injected with anti-A? neutralizing antibodies show decreased fasting blood glucose level and improved insulin sensitivity. Injection of A?42 activates hepatic JAK2/STAT3/SOCS-1 signaling, and neutralization of A? in APPswe/PSEN1dE9 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/PSEN1dE9 mice. Our results demonstrate that A? induces hepatic insulin resistance in vivo via JAK2, suggesting that inhibition of A? signaling is a new strategy toward resolving insulin resistance and T2DM.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC3609589 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature