@article{c494b3ea10654c9998129841e7b6dea0,
title = "A distinct hypothalamus-to-β cell circuit modulates insulin secretion",
abstract = "The central nervous system has long been thought to regulate insulin secretion, an essential process in the maintenance of blood glucose levels. However, the anatomical and functional connections between the brain and insulin-producing pancreatic β cells remain undefined. Here, we describe a functional transneuronal circuit connecting the hypothalamus to β cells in mice. This circuit originates from a subpopulation of oxytocin neurons in the paraventricular hypothalamic nucleus (PVNOXT), and it reaches the islets of the endocrine pancreas via the sympathetic autonomic branch to innervate β cells. Stimulation of PVNOXT neurons rapidly suppresses insulin secretion and causes hyperglycemia. Conversely, silencing of these neurons elevates insulin levels by dysregulating neuronal signaling and secretory pathways in β cells and induces hypoglycemia. PVNOXT neuronal activity is triggered by glucoprivation. Our findings reveal that a subset of PVNOXT neurons form functional multisynaptic circuits with β cells in mice to regulate insulin secretion, and their function is necessary for the β cell response to hypoglycemia.",
keywords = "central nervous system, glucoprivation, hypoglycemia, insulin secretion, oxytocin neurons, pancreatic β cells, paraventricular hypothalamic nucleus, pseudorabies tracing, sympathetic innervation, transneuronal circuit",
author = "Ioannis Papazoglou and Lee, {Ji Hyeon} and Zhenzhong Cui and Chia Li and Gianluca Fulgenzi and Bahn, {Young Jae} and Staniszewska-Goraczniak, {Halina M.} and Pi{\~n}ol, {Ram{\'o}n A.} and Hogue, {Ian B.} and Enquist, {Lynn W.} and Krashes, {Michael J.} and Rane, {Sushil G.}",
note = "Funding Information: We thank Jens B. Bosse and Esteban Engel for assistance with production of Ba2017, Harold Gainer for providing antibodies, Alice Franks for assistance with mouse colony maintenance, Audrey Noguchi and Danielle Springer of the NHLBI Murine Phenotyping Core for glucose telemetry implantation surgeries, and the NHLBI Genomics Core for RNA-seq analyses support. We thank Marc Reitman, Clifton Bogardus, Kevin Hall, Aaron Cypess, Claire-Marie Vacher, and Ramana V. Tantravahi for feedback and critical reading of the manuscript. This research was supported by the Intramural Research Program (DK055105, DK055107, and DK075073 to S.G.R. and DK075087 to M.J.K.) of the NIDDK, NIH. S.G.R. and I.P. conceived and designed the study. H.M.S.-G. I.B.H. and L.W.E. designed and provided the Ba2017 and Ba2001 virus. J.-H.L. performed pancreatic viral injections. I.P. performed all histological and microscopy analyses. Z.C. performed stereotaxic brain injections. J.-H.L. and I.P. performed insulin and glucose testing and measurements. J.-H.L. carried out islet isolation. Y.J.B. performed RNA sequencing experiments, and I.P. contributed to the analysis. G.F. conducted the electron microscopy experiments, and I.P. analyzed the images. C.L. and M.J.K. performed fiber photometry experiments and assisted I.P. with data analyses. R.A.P. assisted with telemetry data acquisition and analysis. R.A.P. and M.J.K. provided input on the project. I.P. performed all statistical analyses and figure designs. I.P. and S.G.R. wrote the manuscript. The authors declare no competing interests. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. Funding Information: We thank Jens B. Bosse and Esteban Engel for assistance with production of Ba2017, Harold Gainer for providing antibodies, Alice Franks for assistance with mouse colony maintenance, Audrey Noguchi and Danielle Springer of the NHLBI Murine Phenotyping Core for glucose telemetry implantation surgeries, and the NHLBI Genomics Core for RNA-seq analyses support. We thank Marc Reitman, Clifton Bogardus, Kevin Hall, Aaron Cypess, Claire-Marie Vacher, and Ramana V. Tantravahi for feedback and critical reading of the manuscript. This research was supported by the Intramural Research Program ( DK055105 , DK055107 , and DK075073 to S.G.R. and DK075087 to M.J.K.) of the NIDDK , NIH. Publisher Copyright: {\textcopyright} 2021",
year = "2022",
month = feb,
day = "1",
doi = "10.1016/j.cmet.2021.12.020",
language = "English (US)",
volume = "34",
pages = "285--298.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "2",
}