期刊
CELL
卷 162, 期 6, 页码 1404-1417出版社
CELL PRESS
DOI: 10.1016/j.cell.2015.08.032
关键词
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资金
- DFG [BR 1492/7-1, TRR134]
- Helmholtz Alliance ICEMED (Imaging and Curing Environmental Metabolic Diseases) through the Initiative and Networking Fund of the Helmholtz Association
- European Union Seventh Framework Programme (FP7) [266408]
- Humboldt-Bayer program of the Alexander Von Humboldt foundation
- Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD)
Activation of orexigenic AgRP-expressing neurons in the arcuate nucleus of the hypothalamus potently promotes feeding, thus defining new regulators of AgRP neuron activity could uncover potential novel targets for obesity treatment. Here, we demonstrate that AgRP neurons express the purinergic receptor 6 (P2Y6), which is activated by uridine-diphosphate (UDP). In vivo, UDP induces ERK phosphorylation and cFos expression in AgRP neurons and promotes action potential firing of these neurons in brain slice recordings. Consequently, central application of UDP promotes feeding, and this response is abrogated upon pharmacologic or genetic inhibition of P2Y6 as well as upon pharmacogenetic inhibition of AgRP neuron activity. In obese animals, hypothalamic UDP content is elevated as a consequence of increased circulating uridine concentrations. Collectively, these experiments reveal a potential regulatory pathway in obesity, where peripheral uridine increases hypothalamic UDP concentrations, which in turn can promote feeding via PY6-dependent activation of AgRP neurons.
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