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Tyrosine Hydroxylase‐Positive Neurons in the Hypothalamic Paraventricular Nucleus Modulate Glucose Homeostasis in Mice
Author(s) -
Souza Lucas,
Gayban Ariana Julia,
Earley Yumei
Publication year - 2021
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.2021.35.s1.02235
Subject(s) - medicine , endocrinology , tyrosine hydroxylase , cre recombinase , hypothalamus , glucose homeostasis , receptor , tryptophan hydroxylase , chemistry , biology , dopamine , diabetes mellitus , serotonin , biochemistry , genetically modified mouse , transgene , insulin resistance , gene , serotonergic
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. 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. The 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 after AAV injection, mice were implanted with telemetry glucose transmitters (HD‐XG, DSI) to monitor blood glucose (BG) levels. To activate or inhibit the TH PVN neuronal activity, Clozapine‐N‐oxide (CNO, 3 mg/Kg) or vehicle were administered (i.p.) and BG was monitored by telemetry. We found that activation of TH PVN neurons by CNO in hM3Dq‐LoxP mice decreased baseline blood glucose compared with the vehicle (ΔBG: ‐9.8 ± 0.2 mg/dL vs. 0.5 ± 0.1 mg/dL, n=5, p <0.0001); on the other hand, inhibition of TH PVN neurons by CNO in the hM4Di‐LoxP mice increased baseline blood glucose levels compared with the vehicle (ΔBG: 12.2 ± 0.2 mg/dL vs. 0.6 ± 0.3 mg/dL, n=3, p <0.0001). To exam 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 CNO or vehicle. We found that activation of TH PVN neurons by CNO improved glucose clearance after the glucose loading compared with vehicle ( AUC: 3028.0±53.0 vs. 6021.0±102.0, p <0.001, 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.