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 Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education), Chongqing Medical University, Chongqing, China
- 2The Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
- 3Technology Transfer Center, University of Michigan, Ann Arbor, MI
- 4Division of Endocrinology, Diabetes and Metabolism and the Clinical Research Center, Temple University School of Medicine, Philadelphia, PA
- Corresponding authors: Ling Li, , and Gangyi Yang, .
D.W., M.Y., and Y.C. contributed equally to this project.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0899/-/DC1.
- Received June 7, 2013.
- Accepted December 11, 2013.
- © 2014 by the American Diabetes Association.
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