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 using an adenoviral-mediated RNAi. Using 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 both normal chow diet (NCD)- and high fat diet (HFD)-fed rats. The change of hepatic glucose fluxes in the hypothalamic nesfatin-1/NUCB2 knockdown rats was accompanied by increased hepatic levels of G-6-Pase and PEPCK and decreased insulin receptor (InsR), insulin receptor substrate 1 (IRS-1), and AKT kinase (AKT) 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 (SOCS3) levels. These results demonstrated that hypothalamic nesfatin-1/NUCB2 plays an important role in glucose homeostasis and hepatic insulin sensitivity, which at least in part, is associated with the activation of the mTOR-STAT3 signaling pathway.
* These authors contributed equally to this project.
- Received June 7, 2013.
- Accepted December 10, 2013.
- © 2014 by the American Diabetes Association.
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