Neurons in the brainstem dorsal vagal complex integrate neural and humoral signals to coordinate autonomic output to viscera that regulate a variety of physiological functions, but how this circuitry regulates metabolism is murky. We tested the hypothesis that premotor, GABAergic neurons in the nucleus tractus solitarius (NTS) form a hindbrain micro-circuit with preganglionic parasympathetic motorneurons of the dorsal motor nucleus of the vagus (DMV) that is capable of modulating systemic blood glucose concentration. In vitro, neuronal activation or inhibition using either excitatory or inhibitory designer receptor exclusively activated by designer drugs (DREADDs) constructs expressed in GABAergic NTS neurons increased or decreased, respectively, action potential firing of GABAergic NTS neurons and downstream synaptic inhibition of the DMV. In vivo, DREADD-mediated activation of GABAergic NTS neurons increased systemic blood glucose concentration, whereas DREADD-mediated silencing of these neurons was without effect. The DREADD-induced hyperglycemia was abolished by blocking peripheral muscarinic receptors, consistent with the hypothesis that altered parasympathetic drive mediated the response. This effect was paralleled by elevated serum glucagon and hepatic phosphoenolpyruvate carboxykinase 1 (PEPCK1) expression, without affecting insulin levels or muscle metabolism. Activity in a hindbrain inhibitory microcircuit is sufficient to modulate systemic glucose concentration, independent of insulin secretion or utilization.
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This work was supported by NIH grant R01 DK056132 to B.N.S. and AHA SDG 16SDG26590000 to C.R.B. The collection and analysis of serum insulin and glucagon was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR001998.
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Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-39490-x.
Boychuk, Carie R.; Smith, Katalin Cs.; Peterson, Laura E.; Boychuk, Jeffery A.; Butler, Corwin R.; Derera, Isabel D.; McCarthy, John J.; and Smith, Bret N., "A Hindbrain Inhibitory Microcircuit Mediates Vagally-Coordinated Glucose Regulation" (2019). Physiology Faculty Publications. 145.