title: Amyloid-β induces hepatic insulin resistance in vivo via JAK2.
abstract: Amyloid-β (Aβ), 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). Aβ 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 Aβ42 exhibit increased fasting blood glucose level, impaired insulin tolerance, and hepatic insulin signaling. Moreover, the APPswe/PSEN1dE9 AD model mice intraperitoneally injected with anti-Aβ neutralizing antibodies show decreased fasting blood glucose level and improved insulin sensitivity. Injection of Aβ42 activates hepatic JAK2/STAT3/SOCS-1 signaling, and neutralization of Aβ 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 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.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ben
authors.initials: B
authors.lastname: Zhou
authors.forename: Bo
authors.initials: B
authors.lastname: Deng
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.forename: Jingxia
authors.initials: J
authors.lastname: Wu
authors.forename: Yuangao
authors.initials: Y
authors.lastname: Wang
authors.forename: Yingying
authors.initials: Y
authors.lastname: Le
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Zhai
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000145:classification / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D007274:Injections, Intraperitoneal; D007333:Insulin Resistance / Q000502:physiology*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001786:Blood Glucose; D050796:STAT3 Transcription Factor; C491590:Socs1 protein, mouse; C494087:Stat3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2