Abstract
Glucokinase (GK) is highly expressed in the hypothalamic paraventricular nucleus (PVN); however, its role is currently unknown. We found that GK in the PVN acts as part of a glucose-sensing mechanism within the PVN that regulates glucose homeostasis by controlling glucagon-like peptide 1 (GLP-1) release. GLP-1 is released from enteroendocrine L cells in response to oral glucose. Here we identify a brain mechanism critical to the release of GLP-1 in response to oral glucose. We show that increasing expression of GK or injection of glucose into the PVN increases GLP-1 release in response to oral glucose. On the contrary, decreasing expression of GK or injection of nonmetabolizable glucose into the PVN prevents GLP-1 release. Our results demonstrate that gluco-sensitive GK neurons in the PVN are critical to the response to oral glucose and subsequent release of GLP-1.
Highlights
The hypothalamic paraventricular nucleus (PVN) is known to have roles in the regulation of energy homeostasis and is a key site for the regulation of the endocrine system
Using rAAV to alter GK expression results in long-term changes in GK activity. To investigate whether these long-term changes in GK activity in the PVN were necessary to alter glucagon-like peptide 1 (GLP-1) levels during an oGTT, we investigated the impact of acute changes in PVN GK activity
We investigated the role of PVN GK using our previously validated recombinant adeno-associated virus 2 (rAAV-2) to increase GK activity in the PVN
Summary
The hypothalamic paraventricular nucleus (PVN) is known to have roles in the regulation of energy homeostasis and is a key site for the regulation of the endocrine system. Neurons from the PVN project to several other regions of the brain, including the nucleus tractus solitarius [1, 2]. GK within the central nervous system (CNS) is expressed in neurons, astrocytes, and tanycytes. In neurons it forms part of the glucose-sensing mechanism and is coexpressed with GLUT2 and ATP-sensitive potassium channels (KATP) [7]. GK is expressed in numerous hypothalamic nuclei, including the ventromedial nucleus (VMN), arcuate nucleus (ARC), and PVN [8, 9]. Given the sparsity of data on the PVN’s role in glucose homeostasis and because GK is expressed in the PVN, and this nucleus is known to have extensive neuronal connections to the pancreas [16,17,18], we sought to investigate the role of glucose sensing in the PVN in glucose homeostasis
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