AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons

Claret, M. et al. (2007) AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. Journal of Clinical Investigation, 117(8), pp. 2325-2336. (doi: 10.1172/JCI31516)

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Abstract

Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMCα2KO and AgRPα2KO mice lacking AMPKα2 in proopiomelanocortin– (POMC-) and agouti-related protein–expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMCα2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRPα2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPKα2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMCα2KO and AgRPα2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Selman, Professor Colin
Authors: Claret, M., Smith, M.A., Batterham, R.L., Selman, C., Choudhury, A.I., Fryer, L.G.D., Clements, M., Al-Qassab, H., Heffron, H., Xu, A.W., Speakman, J.R., Barsh, G.S., Viollet, B., Vaulont, S., Ashford, M.L.J., Carling, D., and Withers, D.J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:Journal of Clinical Investigation
Publisher:Americal Society for Clinical Investigation
ISSN:0021-9738
ISSN (Online):1558-8238
Copyright Holders:Copyright © 2007 American Society for Clinical Investigation
First Published:First published in Journal of Clinical Investigation 117(8):2325-2336
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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