Abstract
Evidence has mounted that insulin can be synthesized in various brain regions, including the hypothalamus. However, the distribution and functions of insulin-expressing cells in the hypothalamus remain elusive. Herein, we show that in the mouse hypothalamus, the perikarya of insulin-positive neurons are located in the paraventricular nucleus (PVN) and their axons project to the median eminence; these findings define parvocellular neurosecretory PVN insulin neurons. Contrary to corticotropin-releasing hormone expression, insulin expression in the PVN was inhibited by restraint stress (RS) in both adult and young mice. Acute RS–induced inhibition of PVN insulin expression in adult mice decreased both pituitary growth hormone (Gh) mRNA level and serum GH concentration, which were attenuated by overexpression of PVN insulin. Notably, PVN insulin knockdown or chronic RS in young mice hindered normal growth via the downregulation of GH gene expression and secretion, whereas PVN insulin overexpression in young mice prevented chronic RS–induced growth retardation by elevating GH production. Our results suggest that in both normal and stressful conditions, insulin synthesized in the parvocellular PVN neurons plays an important role in the regulation of pituitary GH production and body length, unveiling a physiological function of brain-derived insulin.
Highlights
Insulin secreted from pancreatic β cells can cross the blood-brain barrier and dominates the overall insulin content in the brain [1]
A single-cell quantitative reverse transcription–polymerase chain reaction study demonstrated that insulin 2 (Ins2) mRNA is present in GABAergic neurogliaform cells in the cerebral cortex of the rat [7]
To verify the colocalization of Ins2 mRNA and proinsulin protein within the same paraventricular nucleus (PVN) cells, we monitored β-gal expression in the nucleus as a surrogate marker of Ins2 gene expression because the coding sequencing of the Ins2 gene was replaced with LacZ gene in the Ins2-KO mice used in our study [5]
Summary
Insulin secreted from pancreatic β cells can cross the blood-brain barrier and dominates the overall insulin content in the brain [1]. In situ hybridization and immunohistochemistry studies revealed that insulin is produced in the CA1 and CA3 pyramidal neurons and dentate granule neurons in the adult mammalian hippocampus [8,9,10]. These findings suggest that local synthesis might be an alternative source of brain insulin, but the physiological role of brain-derived insulin has not been clarified. Several brain regions have been suggested to possess the capacity for insulin production, the existence of insulin-expressing cells in the hypothalamus remains controversial.
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