Hypothalamic Nesfatin-1/NUCB2 Knockdown Augments Hepatic Gluconeogenesis That Is Correlated With Inhibition of mTOR-STAT3 Signaling Pathway in Rats

  1. Gangyi Yang1
  1. 1Department of Endocrinology, Second Affiliated Hospital, and Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education), Chongqing Medical University, Chongqing, China
  2. 2The Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
  3. 3Technology Transfer Center, University of Michigan, Ann Arbor, MI
  4. 4Division of Endocrinology, Diabetes and Metabolism and the Clinical Research Center, Temple University School of Medicine, Philadelphia, PA
  1. Corresponding authors: Ling Li, liling31{at}hotmail.com, and Gangyi Yang, gangyiyang{at}163.com.
  1. D.W., M.Y., and Y.C. contributed equally to this project.

Abstract

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.

Footnotes

  • Received June 7, 2013.
  • Accepted December 11, 2013.

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  1. Diabetes vol. 63 no. 4 1234-1247
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