Central dopamine D2 receptors regulate plasma glucose levels in mice through autonomic nerves

Abstract

Recent evidence suggests that the central nervous system (CNS) regulates plasma glucose levels, but the underlying mechanism is unclear. The present study investigated the role of dopaminergic function in the CNS in regulation of plasma glucose levels in mice. I.c.v. injection of neither the dopamine D1 receptor agonist SKF 38393 nor the antagonist SCH 23390 influenced plasma glucose levels. In contrast, i.c.v. injection of both the dopamine D2 receptor agonist quinpirole and the antagonist l-sulpiride increased plasma glucose levels. Hyperglycemia induced by quinpirole and l-sulpiride was absent in dopamine D2 receptor knockout mice. I.c.v. injection of quinpirole and l-sulpiride each increased mRNA levels of hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, which are the key enzymes for hepatic gluconeogenesis. Systemic injection of the β2 adrenoceptor antagonist ICI 118,551 inhibited hyperglycemia induced by l-sulpiride, but not by quinpirole. In contrast, hyperglycemia induced by quinpirole, but not by l-sulpiride, was inhibited by hepatic vagotomy. These results suggest that stimulation of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through parasympathetic nerves, whereas inhibition of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through sympathetic nerves.

Effect of TLR4/MyD88/NF‐kB axis in paraventricular nucleus on ventricular arrhythmias induced by sympathetic hyperexcitation in post‐myocardial infarction rats

“… 4 Under hypertensive conditions, the PVN activates and releases NE, 23 an excitatory neurotransmitter, thereby promoting sympathetic output. 24 , 25 In studying diseases such as memory impairment and neurological damage after cerebral ischaemia‐reperfusion, animal models of cerebral ischaemic stroke reflect that the TLR4/MyD88/NF‐kB axis is involved in neuroinflammation. 26 , 27 We performed a study on the role of TLR4 in the mechanism of PVN‐mediated sympathetic activation after MI.…”

“…Studies have shown that many cardiovascular diseases, such as MI, HF and hypertension, are characterized by reduced cardiac function due to peripheral inflammation associated with increased central sympathetic tone, while neuroinflammation of the PVN in turn leads to increased central sympathetic tone 4 . Under hypertensive conditions, the PVN activates and releases NE, 23 an excitatory neurotransmitter, thereby promoting sympathetic output 24,25 . In studying diseases such as memory impairment and neurological damage after cerebral ischaemia‐reperfusion, animal models of cerebral ischaemic stroke reflect that the TLR4/MyD88/NF‐kB axis is involved in neuroinflammation 26,27 .…”

Nitrate exposure reprograms hepatic amino acid and nutrient sensing pathways prior to exercise: A metabolomic and transcriptomic investigation in zebrafish (Danio rerio)

“…About 50% of dopamine is produced in the gut by enteric neurons and intestinal epithelial cells, leading to increased dopamine concentration in the hepatic portal vein ( Xue et al, 2018 ). Interestingly, a study in mice showed that stimulation of central dopamine D 2 receptors increases plasma glucose levels by increasing hepatic glucose production through parasympathetic nerves ( Ikeda et al, 2020 ). The increased abundance of dopamine in liver may be another mechanism by which nitrate exposure mediates hepatic glucose output.…”

The role of hypothalamic endoplasmic reticulum stress in schizophrenia and antipsychotic-induced weight gain: A narrative review

“…Hypothalamic DRD2 signaling plays an essential role in the regulation of food intake, body weight, and glucose metabolism (Yonemochi et al, 2019;Ikeda et al, 2020). Several studies have proved that a decline in central dopaminergic activity significantly influences metabolic parameters such as BMI, glucose, and lipid metabolism in humans (Brunerova et al, 2013).…”

“…A recent clinical study reported a reduction in hypothalamic dopamine D2/D3 receptor (DRD2/DRD3) availability (examined by 18 F-fluorodeoxyglucose and 18 F-fallypride positron emission tomography [PET] imaging) in unmedicated patients with SCZ (Mitelman et al, 2020), suggesting the involvement of hypothalamic DRD2/DRD3 signaling in SCZ. Reduced DRD2 signaling in the hypothalamus is known to increase food intake, body weight, and regulate glucose metabolism (Ikeda et al, 2020), suggesting that the reduced DRD2 signaling may also be related to SCZ-related metabolic disorders such as increased BMI and abnormalities in glucose metabolism. However, the mechanisms are currently incompletely understood.…”