Glucose sensing mechanisms in hypothalamic cell models: Glucose inhibition of AgRP synthesis and secretion

Glucose-sensing neurons play a role in energy homeostasis, yet how orexigenic neurons sense glucose remains unclear. As models of glucose-inhibited (GI) neurons, mHypoE-29/1 and mHypoA-NPY/GFP cells express the essential orexigenic neuropeptide AgRP and glucose sensing machinery. Exposure to increasing concentrations of glucose or the glucose analog 2-deoxyglucose (2-DG) results in a decrease in AgRP mRNA levels. Taste receptor, Tas1R2 mRNA expression was reduced by glucose, whereas 2-DG reduced Tasl R3 mRNA levels. Increasing glucose concentrations elicited a rise in Akt and neuronal nitric oxide synthase (nNOS) phosphorylation, CaMKKO levels, and a reduction of AMP-kinase alpha phosphorylation. Inhibitors of NOS and the cystic fibrosis transmembrane conductance regulator (CFTR) prevented a decrease in AgRP secretion with glucose, suggesting a pivotal role for nNOS and the CFTR in glucosesensing. These models possess the hallmark characteristics of GI neurons, and can be used to disentangle the mechanisms by which orexigenic neurons sense glucose. (C) 2013 Elsevier Ireland Ltd. All rights reserved.