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Tyrosine Hydroxylase‐Positive Neurons in the Hypothalamic Paraventricular Nucleus Modulate Blood Glucose Levels in Mice
Author(s) -
Souza Lucas A. C.,
Gayban Ariana J.,
Feng Earley Yumei
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.r3645
Subject(s) - medicine , endocrinology , tyrosine hydroxylase , rostral ventrolateral medulla , brainstem , hypothalamus , adrenergic neurons , dopaminergic , biology , receptor , chemistry , neuroscience , dopamine , central nervous system , medulla oblongata , adrenergic
Tyrosine hydroxylase (TH)‐positive neurons in the paraventricular nucleus of the hypothalamus (PVN), termed TH PVN neurons, have emerged as key metabolic regulators. Recent studies showed that TH PVN neurons are mostly Gamma‐aminobutyric acid (GABA)ergic and/or dopaminergic. Previous results from our laboratory indicate that TH PVN neurons project to brainstem autonomic regulatory nuclei, such as nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM). However, it is not known if TH PVN neurons play a role in blood glucose regulation. We hypothesize that TH PVN neurons are key regulators of blood glucose. To test our hypothesis, we used adeno‐associated virus serotype 2 (AAV2)‐mediated Cre‐recombinase driven by a rat TH promoter (AAV2‐TH‐Cre), in combination with chemogenetic approach (Designer Receptors Exclusively Activated by Designer Drugs, DREADD) to activate or inhibit TH PVN neurons and continuously monitored blood glucose levels using telemetry system. hM3Dq‐LoxP (excitatory‐DREADD) and hM4Di‐LoxP (inhibitory‐DREADD) mice, 10‐14 weeks old, were bilaterally microinjected with AAV2‐TH‐Cre into the PVN. One month following AAV injection, mice were implanted with telemetry glucose transmitters (HD‐XG, DSI) to monitor blood glucose (BG) levels. To activate or inhibit TH PVN neuronal activity, Clozapine‐N‐oxide (CNO, 1 mg/Kg) or vehicle were administered (i.p.) and BG was monitored by telemetry. To examine the functional role of TH PVN neurons at baseline and avoid the influence of feeding on blood glucose levels, mice were fasted for 2 hours and fasting was maintained throughout the experiment. We found that activation of TH PVN neurons by CNO in hM3Dq‐LoxP mice did not alter baseline blood glucose (n=5); on the other hand, inhibition of TH PVN neurons by CNO in hM4Di‐LoxP mice increased baseline blood glucose levels compared with vehicle only in male mice ( Male: ΔBG: 31.6 ± 8.6 mg/dL vs. 11.0 ± 6.7 mg/dL, n=4, p =0.03; Female: ΔBG: 11.0 ± 7.4 mg/dL vs. 7.3 ± 5.9 mg/dL, n=4, p =0.16). To study the functional role of TH PVN neurons on whole body glucose handling, mice were fasted overnight and simultaneously injected with glucose (1 g/Kg) and either vehicle or CNO. We found that activation of TH PVN neurons by CNO improved glucose clearance after glucose overload when compared with vehicle ( AUC: 3133.0±109.0 vs. 6021.0±102.0, p <0.0001, n=3) in hM3Dq‐LoxP mice. In summary, our data suggest that TH PVN neurons negatively regulate blood glucose possibly by their GABAergic input to downstream neural circuits. We conclude that TH PVN neurons play a functional role in the regulation of glucose homeostasis; while the mechanisms remain to be determined.