Hypothalamic nesfatin-1/NUCB2 knockdown augments hepatic gluconeogenesis that is correlated with inhibition of mTOR-STAT3 signaling pathway in rats.
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.
Department of Endocrinology, Second Affiliated Hospital, and Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education), Chongqing Medical University, Chongqing, China.
Dandong
D
Wu
Mengliu
M
Yang
Yang
Y
Chen
Yanjun
Y
Jia
Zhongmin Alex
ZA
Ma
Guenther
G
Boden
Ling
L
Li
Gangyi
G
Yang
D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D059305:Diet, High-Fat; D004435:Eating; D055785:Gene Knockdown Techniques; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D007276:Injections, Intraventricular; D007328:Insulin / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D000080866:Nucleobindins; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; C000630652:Nucb1 protein, rat; D000080866:Nucleobindins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose