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Diabetologia

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01-01-2007 | Article

Inhibition by glucose or leptin of hypothalamic neurons expressing neuropeptide Y requires changes in AMP-activated protein kinase activity

Authors: P. D. Mountjoy, S. J. Bailey, G. A. Rutter

Published in: Diabetologia | Issue 1/2007

Abstract

Aims/hypothesis

Changes in the activity of glucose-excited and glucose-inhibited neurons within the basomedial hypothalamus are key to the central regulation of satiety. However, the molecular mechanisms through which these cells respond to extracellular stimuli remain poorly understood. Here, we investigate the role of 5′-AMP-activated protein kinase (AMPK), a trimeric complex encoded by seven distinct genes of the PRKA family, in the responses to glucose and leptin of each cell type.

Methods

The activity of isolated rat basomedial hypothalamic neurons was assessed by: (1) recording cellular voltage responses under current clamp; (2) measuring intracellular free Ca²⁺ with fluo-3 or fura-2; and (3) developing a neuropeptide Y (NPY) promoter-driven adenovirally produced ratiometric ‘pericam’ (a green fluorescent protein-based Ca²⁺ sensor) to monitor [Ca²⁺] changes selectively in NPY-positive neurons.

Results

The stimulatory effects of decreased (0 or 1.0 vs 15 mmol/l) glucose on glucose-inhibited neurons were mimicked by the AMPK activator, 5-amino-imidazole-4-carboxamide riboside (AICAR) and blocked by the inhibitor Compound C. Similarly, AICAR reversed the inhibitory effects of leptin in the majority of glucose-inhibited neurons. The responses to glucose of Npy-expressing cells, which represented ∼40 % of all glucose-inhibited neurons, were also sensitive to Compound C or AICAR. Forced changes in AMPK activity had no effect on glucose-excited and non-glucose-responsive neurons.

Conclusions/interpretation

Changes in AMPK activity are involved in the responses of glucose-inhibited neurons to large fluctuations in glucose concentration, and possibly also to leptin. This mechanism may contribute to the acute reduction of electrical activity and Ca²⁺ oscillation frequency in these, but not other neurons, in the basomedial hypothalamus.

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Title: Inhibition by glucose or leptin of hypothalamic neurons expressing neuropeptide Y requires changes in AMP-activated protein kinase activity
Authors: P. D. Mountjoy
S. J. Bailey
G. A. Rutter
Publication date: 01-01-2007
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 1/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0473-3

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Abstract

Aims/hypothesis

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