Hypothalamic Nesfatin-1/NUCB2 Knockdown Augments Hepatic Gluconeogenesis that is Correlated with Inhibition of mTOR-STAT3 Signaling Pathway in Rats
- Dandong Wu1,*,
- Mengliu Yang1,*,
- Yang Chen1,*,
- Yanjun Jia2,
- Zhongmin Alex Ma3,
- Guenther Boden4,
- Ling Li1⇑ and
- Gangyi Yang1⇑
- 1Department of Endocrinology, Second Affiliated Hospital and M.O.E Key Laboratory of Laboratory Diagnostics, Chongqing Medical University, 400010 Chongqing, China
- 2The Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, 400016 Chongqing, China
- 3Technology Transfer Center, University of Michigan, Ann Arbor, MI 48109, USA
- 4The Division of Endocrinology/Diabetes/Metabolism and the Clinical Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
- Corresponding author: Gangyi Yang and Ling Li, E-mail: ;
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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