(Pro)renin receptor signaling in hypothalamic tyrosine hydroxylase neurons is required for obesity-associated glucose metabolic impairment
Shiyue Pan, Lucas A.C. Souza, Caleb J. Worker, Miriam E. Reyes Mendez, Ariana Julia B. Gayban, Silvana G. Cooper, Alfredo Sanchez Solano, Richard N. Bergman, Darko Stefanovski, Gregory J. Morton, Michael W. Schwartz, Yumei Feng Earley
Shiyue Pan, Lucas A.C. Souza, Caleb J. Worker, Miriam E. Reyes Mendez, Ariana Julia B. Gayban, Silvana G. Cooper, Alfredo Sanchez Solano, Richard N. Bergman, Darko Stefanovski, Gregory J. Morton, Michael W. Schwartz, Yumei Feng Earley
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Research Article Endocrinology Metabolism

(Pro)renin receptor signaling in hypothalamic tyrosine hydroxylase neurons is required for obesity-associated glucose metabolic impairment

Abstract

Glucose homeostasis is achieved via complex interactions between the endocrine pancreas and other peripheral tissues and glucoregulatory neurocircuits in the brain that remain incompletely defined. Within the brain, neurons in the hypothalamus appear to play a particularly important role. Consistent with this notion, we report evidence that (pro)renin receptor (PRR) signaling within a subset of tyrosine hydroxylase (TH) neurons located in the hypothalamic paraventricular nucleus (PVNTH neurons) is a physiological determinant of the defended blood glucose level. Specifically, we demonstrate that PRR deletion from PVNTH neurons restores normal glucose homeostasis in mice with diet-induced obesity (DIO). Conversely, chemogenetic inhibition of PVNTH neurons mimics the deleterious effect of DIO on glucose. Combined with our finding that PRR activation inhibits PVNTH neurons, these findings suggest that, in mice, (a) PVNTH neurons play a physiological role in glucose homeostasis, (b) PRR activation impairs glucose homeostasis by inhibiting these neurons, and (c) this mechanism plays a causal role in obesity-associated metabolic impairment.

Authors

Shiyue Pan, Lucas A.C. Souza, Caleb J. Worker, Miriam E. Reyes Mendez, Ariana Julia B. Gayban, Silvana G. Cooper, Alfredo Sanchez Solano, Richard N. Bergman, Darko Stefanovski, Gregory J. Morton, Michael W. Schwartz, Yumei Feng Earley

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Figure 6

Chemogenetic inhibition of PVNTH neurons increases blood glucose in both male and female mice.

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Chemogenetic inhibition of PVNTH neurons increases blood glucose in both...
(A) Schematic diagram of 1-time injections of either AAV2-TH-GFP (control virus, non-DREADD) or AAV2-rTH-Cre (DREADD) into the PVN of hM4Di-LoxP mice. One month after the AAV2 injection, mice were implanted with HD-XG telemetric glucose transmitters followed by continuous glucose monitoring (CGM). (B) Representative traces of CGM following injection of either vehicle or clozapine N-oxide (CNO, 1 mg/Kg) for 3 hours in DREADD mice. (C and D) Summary data of blood glucose levels following injection of either vehicle or CNO at 15 and 60 minutes in male mice (n = 6). (E and F) Summary data of blood glucose levels following injection of either vehicle or CNO at 15 and 60 minutes in female mice (n = 9). (G) Representative traces of CGM following injection of either vehicle or clozapine N-oxide (CNO, 1 mg/Kg) for 3 hours in non-DREADD mice. (H and I) Summary data of blood glucose levels following injection of either vehicle or CNO at 15 and 60 minutes in both male (n = 3) and female (n = 4) non-DREADD mice. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, 2-tailed paired Student’s t test was used.