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

Marc Claret, Mark A. Smith, Rachel L. Batterham, Colin Selman, Agharul I. Choudhury, Lee G.D. Fryer, Melanie Clements, Hind Al-Qassab, Helen Heffron, Allison W. Xu, John R. Speakman, Gregory S. Barsh, Benoit Viollet, Sophie Vaulont, Michael L. J. Ashford, David Carling, Dominic J. Withers

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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 POMCa2KO and AgRPa2KO mice lacking AMPKa2 in proopiomelanocortin– (POMC-) and agouti-related protein–expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMCa2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRPa2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPKa2-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 POMCa2KO and AgRPa2KO 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.
    Original languageEnglish
    Pages (from-to)2325-2336
    Number of pages12
    JournalJournal of Clinical Investigation
    Volume117
    Issue number8
    DOIs
    Publication statusPublished - Aug 2007

    Keywords

    • Hypothalamic AMP-activated protein kinase (AMPK)
    • AMPK
    • Energy metabolism physiology
    • Homeostasis physiology
    • Hypothalamus metabolism
    • Intercellular signaling peptides and proteins metabolism
    • Multienzyme complexes metabolism
    • Neurons metabolism
    • Pro-opiomelanocortin metabolism
    • Protein-serine-threonine kinases metabolism

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  • Cite this

    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., & Withers, D. J. (2007). AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. Journal of Clinical Investigation, 117(8), 2325-2336. https://doi.org/10.1172/JCI31516