Nesfatin-1 action in the brain increases insulin sensitivity through Akt/AMPK/TORC2 pathway in diet-induced insulin resistance.
Nesfatin-1, derived from nucleobindin 2, was recently identified as an anorexigenic signal peptide. However, its neural role in glucose homeostasis and insulin sensitivity is unknown. To evaluate the metabolic impact and underlying mechanisms of central nesfatin-1 signaling, we infused nesfatin-1 in the third cerebral ventricle of high-fat diet (HFD)-fed rats. The effects of central nesfatin-1 on glucose metabolism and changes in transcription factors and signaling pathways were assessed during euglycemic-hyperinsulinemic clamping. The infusion of nesfatin-1 into the third cerebral ventricle markedly inhibited hepatic glucose production (HGP), promoted muscle glucose uptake, and was accompanied by decreases in hepatic mRNA and protein expression and enzymatic activity of PEPCK in both standard diet- and HFD-fed rats. In addition, central nesfatin-1 increased insulin receptor (InsR)/insulin receptor substrate-1 (IRS-1)/AMP-dependent protein kinase (AMPK)/Akt kinase (Akt)/target of rapamycin complex (TORC) 2 phosphorylation and resulted in an increase in Fos immunoreactivity in the hypothalamic nuclei that mediate glucose homeostasis. Taken together, these results reveal what we believe to be a novel site of action of nesfatin-1 on HGP and the PEPCK/InsR/IRS-1/AMPK/Akt/TORC2 pathway and suggest that hypothalamic nesfatin-1 action through a neural-mediated pathway can contribute to increased peripheral and hepatic insulin sensitivity by decreasing gluconeogenesis and promoting peripheral glucose uptake in vivo.
Department of Endocrinology, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Mengliu
M
Yang
Zhihong
Z
Zhang
Chong
C
Wang
Ke
K
Li
Shengbing
S
Li
Guenther
G
Boden
Ling
L
Li
Gangyi
G
Yang
D000263:Adenylate Kinase / Q000502:physiology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D059305:Diet, High-Fat; D005947:Glucose / Q000378:metabolism; D007276:Injections, Intraventricular; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D000080866:Nucleobindins; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology
C545700:CRTC2 protein, rat; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D055504:Insulin Receptor Substrate Proteins; D009419:Nerve Tissue Proteins; C000630652:Nucb1 protein, rat; D000080866:Nucleobindins; D015534:Trans-Activators; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose