Release of insulin produced by the choroid plexis is regulated by serotonergic signaling
Caio Henrique Mazucanti, Qing-Rong Liu, Doyle Lang, Nicholas Huang, Jennifer F. O’Connell, Simonetta Camandola, Josephine M. Egan
Caio Henrique Mazucanti, Qing-Rong Liu, Doyle Lang, Nicholas Huang, Jennifer F. O’Connell, Simonetta Camandola, Josephine M. Egan
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Research Article Endocrinology Neuroscience

Release of insulin produced by the choroid plexis is regulated by serotonergic signaling

Abstract

The choroid plexus (ChP) is a highly vascularized tissue found in the brain ventricles, with an apical epithelial cell layer surrounding fenestrated capillaries. It is responsible for the production of most of the cerebrospinal fluid (CSF) in the ventricular system, subarachnoid space, and central canal of the spinal cord, while also constituting the blood-CSF barrier (BCSFB). In addition, epithelial cells of the ChP (EChP) synthesize neurotrophic factors and other signaling molecules that are released into the CSF. Here, we show that insulin is produced in EChP of mice and humans, and its expression and release are regulated by serotonin. Insulin mRNA and immune-reactive protein, including C-peptide, are present in EChP, as detected by several experimental approaches, and appear in much higher levels than any other brain region. Moreover, insulin is produced in primary cultured mouse EChP, and its release, albeit Ca2+ sensitive, is not regulated by glucose. Instead, activation of the 5HT2C receptor by serotonin treatment led to activation of IP3-sensitive channels and Ca2+ mobilization from intracellular storage, leading to insulin secretion. In vivo depletion of brain serotonin in the dorsal raphe nucleus negatively affected insulin expression in the ChP, suggesting an endogenous modulation of ChP insulin by serotonin. Here, we show for the first time to our knowledge that insulin is produced by EChP in the brain, and its release is modulated at least by serotonin but not glucose.

Authors

Caio Henrique Mazucanti, Qing-Rong Liu, Doyle Lang, Nicholas Huang, Jennifer F. O’Connell, Simonetta Camandola, Josephine M. Egan

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Figure 2

Insulin transcript variants and proconvertase RNA are differentially expressed throughout the brain.

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Insulin transcript variants and proconvertase RNA are differentially exp...
(A) Mouse Ins2 gene has 3 transcript variants. (B) Specific insulin transcripts are differentially expressed in the choroid plexus and pancreatic islets. Values are compared with ChP Ins2-1 expression, and results are summarized in Table 1. (C–E) In the brain, all 3 transcript variants are more abundantly expressed in the choroid plexus than any other brain structure. Results are summarized in Table 1. (F) Comparison of insulin expression levels in telencephalic and hindbrain choroid plexus present in the lateral and fourth ventricle, respectively (as depicted in the schematic diagram), reveals higher levels in the posterior ChP, a trend also observed for 2 important enzymes necessary for proinsulin maturation (Ins1: LV ChP mean = 1.206, SEM = 0.1987, 4thV ChP mean = 3.668, SEM = 0.4292, n = 7–8; Ins2-1: LV ChP mean = 1.141, SEM = 0.1536, 4thV ChP mean = 3.550, SEM = 0.4261, n = 6–8; Ins2-3: LV ChP mean = 1.120, SEM = 0.1348, 4thV ChP mean = 2.674, SEM = 0.3501, n = 8–9; Pcsk2: LV ChP mean = 1.002, SEM = 0.02841, 4thV ChP mean = 2.131, SEM = 0.1031, n = 6). Student’s t test, **P < 0.01; ***P < 0.001; ****P < 0.0001. CB, cerebellum; ChP, choroid plexus; CX, cortex; HP, hippocampus; HY, hypothalamus; MB, midbrain; OB, olfactory bulb; PI, pancreatic islets.