UNSPECIFIED. (2005) Activation of hypothalamic ATP-sensitive K+ channels by the aminoguanidine carboxylate BVT.12777. JOURNAL OF NEUROENDOCRINOLOGY, 17 (4). pp. 246-254. ISSN 0953-8194

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Abstract

Derivatives of 3-guanidinopropionic acid, such as leptin, reduce body weight in obese, diabetic mice. We have assessed whether one of these analogues, BVT.12777 activates intracellular signalling pathways in the arcuate nucleus in a manner analogous to leptin and insulin. In addition, because these hormones have been shown to activate K-ATP channels in a subset of arcuate neurones, we examined whether this channel is also a functional endpoint for BVT.12777 in the arcuate nucleus. BVT.12777 transiently increased phosphorylation of MAPK, STAT3, PKB and GSK3, in a manner identical to that observed for leptin and insulin. BVT.12777 also hyperpolarized glucose-responsive neurones by increasing the activity of K-ATP channels. The increase in K-ATP activity driven by BVT.12777 was PI3-kinase independent, unlike leptin and insulin activation of this channel, and could also be elicited in isolated patches. However, K-ATP activity induced by BVT.12777 was dependent on actin filament dynamics, both in intact neurones and isolated patches. Thus, BVT.12777 modulates arcuate neurone K-ATP activity by re-organization of the cytoskeleton, a mechanism that has also been ascribed to leptin and insulin. Consequently, BVT.12777 appears to act as a leptin and insulin mimetic with respect to at least some elements of arcuate neurone intracellular signalling and the activation of K-ATP channels. Resistance to leptin and insulin, associated with obesity has, at least in part, been postulated to be due to aberrant intracellular signalling in arcuate neurones. The data presented here indicate that it may be possible to develop drugs, which by-pass up-stream signalling components associated with adiposity hormone resistance, such as PI3-kinase, but can still induce functional outputs from arcuate neurones by targeting downstream components of the leptin and insulin signalling cascades.

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Journal or Publication Title:	JOURNAL OF NEUROENDOCRINOLOGY
Publisher:	BLACKWELL PUBLISHING LTD
ISSN:	0953-8194
Date:	April 2005
Volume:	17
Number:	4
Number of Pages:	9
Page Range:	pp. 246-254
Identification Number:	10.1111/j.1365-2826.2005.01299.x
Publication Status:	Published
URI:	http://wrap.warwick.ac.uk/id/eprint/7180

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