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 6

VMNCCKBR neurons play a requisite role in the CRR.

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VMNCCKBR neurons play a requisite role in the CRR. (A and B) Blood gluco...
(A and B) Blood glucose values and the calculated AUC during insulin-induced hypoglycemia (0.6 U/kg, i.p.) (A) and in response to glucoprivation with 2-DG (250 mg/kg, i.p.) (B) for CCKBRTT (n = 16) and control (n = 38) mice. Data in the left panels are expressed as the mean ± SEM, and AUC data are given as box-and-whisker plots that show the data spread from minimum to maximum, median, first quartile, and third quartile. *P < 0.05 versus control; time course data were analyzed by repeated-measures ANOVA with Fisher’s LSD post hoc test, and AUC data were analyzed by Student’s t test. (C) Response to repeated (daily for 4 days) glucoprivation with 2-DG (250 mg/kg, i.p.) in CCKBRTT (n = 5) and control (n = 9) mice with glucose measurement during the subsequent 120 minutes on days 1 and 4. Data in the middle panel are expressed as the mean ± SEM, and AUC data are given as box-and-whisker plots showing the data spread from minimum to maximum, median, first quartile, and third quartile. *P < 0.05 versus the control; time course data were analyzed by repeated-measures ANOVA with Fisher’s LSD post hoc test, and AUC data were analyzed by 1-way ANOVA with Fisher’s LSD post hoc test. The different lowercase letters in the plots indicate significant differences (P < 0.05). (D) Response to repeated (daily for 3 days) glucoprivation with 2-DG (250 mg/kg, i.p.) in CCKBRChR2 mice, with glucose levels measured during the subsequent 60 minutes on days 0 and 4. Note that mice from this experiment were the same as those described in Figure 1. Data in the middle panel are expressed as the mean ± SEM, and AUC data are given as box-and-whisker plots showing the data spread from minimum to maximum, median, first quartile, and third quartile; n = 9 for all. *P < 0.05 versus control; time course data were analyzed by repeated-measures ANOVA with Fisher’s LSD post hoc test, and AUC data were analyzed by Student’s t test.