(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 3

Deletion of (pro)renin receptor (PRR) in PVNTH neurons lowers fasting blood glucose (FBG) in HFD-induced obese male mice.

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Deletion of (pro)renin receptor (PRR) in PVNTH neurons lowers fasting bl...
(A) Schematic representation of Cre-LoxP–mediated deletion of PRR in PVNTH neurons in PRR-tdTomato-LoxP mice. Mice bearing both PRR-LoxP and tdTomato-LoxP alleles (PRR-tdTomato-LoxP) received bilateral microinjection directed to the PVN of an AAV-expressing Cre recombinase driven by a rat tyrosine hydroxylase promoter (AAV2-rTH-Cre), while tdTomato-LoxP mice received the AAV2-rTH-Cre virus to the PVN and were used as controls. (B) Schematic diagram of the experimental protocol. Four weeks after viral injection, mice were placed on either a low-fat diet (LFD, 10% calories from fat) or a high-fat diet (HFD, 60% calories from fat). (C–E) Weekly body weight gain, calorie intake, and fasting blood glucose at 6 weeks following exposure to either an HFD or an LFD. n = 4–5 animals/group. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001. Two-way ANOVA with Fisher’s LSD multiple comparisons tests were used.