Abstract
Glucokinase (GK), the hexokinase involved in glucosensing in pancreatic β-cells, is also expressed in arcuate nucleus (AN) neurons and hypothalamic tanycytes, the cells that surround the basal third ventricle (3V). Several lines of evidence suggest that tanycytes may be involved in the regulation of energy homeostasis. Tanycytes have extended cell processes that contact the feeding-regulating neurons in the AN, particularly, agouti-related protein (AgRP), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) neurons. In this study, we developed an adenovirus expressing GK shRNA to inhibit GK expression in vivo. When injected into the 3V of rats, this adenovirus preferentially transduced tanycytes. qRT-PCR and Western blot assays confirmed GK mRNA and protein levels were lower in GK knockdown animals compared to the controls. In response to an intracerebroventricular glucose injection, the mRNA levels of anorexigenic POMC and CART and orexigenic AgRP and NPY neuropeptides were altered in GK knockdown animals. Similarly, food intake, meal duration, frequency of eating events and the cumulative eating time were increased, whereas the intervals between meals were decreased in GK knockdown rats, suggesting a decrease in satiety. Thus, GK expression in the ventricular cells appears to play an important role in feeding behavior.
Highlights
As one of the main centers controlling food intake, the hypothalamus is a structure located in the basal region of the third ventricle (3V), and is composed of neurons and other cells, such as tanycytes, that respond to glucose concentration[1,2,3,4]
The hypothalamus is involved in the control of feeding behavior due to its ability to detect and respond to changes in blood glucose levels[30]
The arcuate nucleus (AN), which is located in the basal region of the hypothalamus, is proximal to the median eminence (ME), a circumventricular organ known to play an important role in homeostatic regulation[31]
Summary
As one of the main centers controlling food intake, the hypothalamus is a structure located in the basal region of the third ventricle (3V), and is composed of neurons (grouped in different nuclei) and other cells, such as tanycytes, that respond to glucose concentration[1,2,3,4]. Tanycytes are polarized, lengthened cells with apical surface differentiations in direct contact with the cerebrospinal fluid (CSF) and long basal processes that come into close contact with neurons from the periventricular nuclei of the basal hypothalamus[5] Based on their morphological and histochemical features, tanycytes have been classified into four subpopulations: α1, α2, β1 and β26. Α2 and β1 tanycytes are localized in the lower lateral wall of the 3V They have extended cell processes that project into the arcuate nucleus (AN) and appear to come into close contact with feeding-regulating neurons, agouti-related protein (AgRP), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) neurons . Alterations in feeding behavior (i.e., decreased satiety) were detected Based on these results, we postulate that hypothalamic GK activity could regulate food intake as part of a glucostatic control system
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