Ventromedial hypothalamic nucleus neuronal subset regulates blood glucose independently of insulin
Jonathan N. Flak, … , David P. Olson, Martin G. Myers Jr.
Jonathan N. Flak, … , David P. Olson, Martin G. Myers Jr.
Published March 5, 2020
Citation Information: J Clin Invest. 2020;130(6):2943-2952. https://doi.org/10.1172/JCI134135.
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Research Article Endocrinology Metabolism

Ventromedial hypothalamic nucleus neuronal subset regulates blood glucose independently of insulin

Abstract

To identify neurons that specifically increase blood glucose from among the diversely functioning cell types in the ventromedial hypothalamic nucleus (VMN), we studied the cholecystokinin receptor B–expressing (CCKBR-expressing) VMN targets of glucose-elevating parabrachial nucleus neurons. Activation of these VMNCCKBR neurons increased blood glucose. Furthermore, although silencing the broader VMN decreased energy expenditure and promoted weight gain without altering blood glucose levels, silencing VMNCCKBR neurons decreased hIepatic glucose production, insulin-independently decreasing blood glucose without altering energy balance. Silencing VMNCCKBR neurons also impaired the counterregulatory response to insulin-induced hypoglycemia and glucoprivation and replicated hypoglycemia-associated autonomic failure. Hence, VMNCCKBR cells represent a specialized subset of VMN cells that function to elevate glucose. These cells not only mediate the allostatic response to hypoglycemia but also modulate the homeostatic setpoint for blood glucose in an insulin-independent manner, consistent with a role for the brain in the insulin-independent control of glucose homeostasis.

Authors

Jonathan N. Flak, Paulette B. Goforth, James Dell’Orco, Paul V. Sabatini, Chien Li, Nadejda Bozadjieva, Matthew Sorensen, Alec Valenta, Alan Rupp, Alison H. Affinati, Corentin Cras-Méneur, Ahsan Ansari, Jamie Sacksner, Nandan Kodur, Darleen A. Sandoval, Robert T. Kennedy, David P. Olson, Martin G. Myers Jr.

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Figure 1

Activation of VMNCCKBR neurons promotes hyperglycemia.

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Activation of VMNCCKBR neurons promotes hyperglycemia. (A) Shown is a re...
(A) Shown is a representative image of the VMN from CckbrCre animals on the Rosa26EGFP-L10a reporter line stained for GFP (green). 3V, third cerebral ventricle; DMH, dorsomedial hypothalamic nucleus; Arc, arcuate nucleus. Scale bar: 100 μm. (B) Experimental schematic showing intra-VMN administration of AAV-DIO-ChR2-eYFP to CckbrCre (n = 9) or Sf1Cre (n = 5) mice to permit the optogenetic activation of VMNCCKBR neurons or all VMN cell populations, respectively. (C and D) Animals were food deprived at the onset of the light cycle and studied 4–5 hours later. Shown is the glycemic response to control or light delivery, along with the calculated AUC. Plasma samples taken after 30 minutes (E, F, and I) or 60 minutes (G, H, and J) of stimulation in CCKBRChR2 mice were analyzed for circulating concentrations of epinephrine (E), norepinephrine (F), corticosterone (G), glucagon (H), and insulin (I and J). Data are plotted as the mean ± SEM (C) or as box-and-whisker plots that show the data spread from minimum to maximum, median, first quartile, and third quartile (D–J). P < 0.05, by 2-way ANOVA with Fisher’s LSD post hoc test (C and D) (the different lowercase letters in the plots in C and D indicate statistical differences); *P < 0.05, by unpaired Student’s t test (E–I).