期刊
DIABETES
卷 63, 期 4, 页码 1234-1247出版社
AMER DIABETES ASSOC
DOI: 10.2337/db13-0899
关键词
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资金
- National Natural Science Foundation of China [30871199, 81270913, 81070640, 30971388, 30771037]
- Ministry of Education of China [20105503110002, 20125503110003]
- Natural Science Foundation Key Project of CQCSTC [cstc2012jj B10022]
- American Diabetes Association [1-10-CT-06]
Nesfatin-1, an 82-amino acid neuropeptide, has recently been characterized as a potent metabolic regulator. However, the metabolic mechanisms and signaling steps directly associated with the action of nesfatin-1 have not been well delineated. We established a loss-of-function model of hypothalamic nesfatin-1/NUCB2 signaling in rats through an adenoviral-mediated RNA interference. With this model, we found that inhibition of central nesfatin-1/NUCB2 activity markedly increased food intake and hepatic glucose flux and decreased glucose uptake in peripheral tissue in rats fed either a normal chow diet (NCD) or a high-fat diet (HFD). The change of hepatic glucose fluxes in the hypothalamic nesfatin-1/NUCB2 knockdown rats was accompanied by increased hepatic levels of glucose-6-phosphatase and PEPCK and decreased insulin receptor, insulin receptor substrate 1, and AKT kinase phosphorylation. Furthermore, knockdown of hypothalamic nesfatin-1 led to decreased phosphorylation of mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) and the subsequent suppressor of cytokine signaling 3 levels. These results demonstrate that hypothalamic nesfatin-1/NUCB2 plays an important role in glucose homeostasis and hepatic insulin sensitivity, which is, at least in part, associated with the activation of the mTOR-STAT3 signaling pathway.
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