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

Research output: Contribution to journalArticle

333 Citations (Scopus)

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 POMC alpha 2KO and AgRP alpha 2KO mice lacking AMPK alpha 2 in proopiomelanocortin- (POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMC alpha 2KO 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 AMPK alpha 2-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 POMC alpha 2KO and AgRP alpha 2KO 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
JournalThe Journal of Clinical Investigation
Volume117
Issue number8
DOIs
Publication statusPublished - 1 Aug 2007

Keywords

  • activated protein-kinase
  • hypothalamic arcuate nucleus
  • diabetes-obesity syndromes
  • fatty-acid oxidation
  • food-intake
  • catalytic subunit
  • upstream kinase
  • skeletal-muscle
  • nervous-system
  • insulin

Cite this

Claret, M., Smith, M. A., Batterham, R. L., Selman, C., Choudhury, A. I., Fryer, L. G. D., ... Withers, D. J. (2007). AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. The Journal of Clinical Investigation, 117(8), 2325-2336. https://doi.org/10.1172/JCI31516

AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. / Claret, Marc; Smith, Mark A.; Batterham, Rachel L.; Selman, Colin; Choudhury, Agharul I.; Fryer, Lee G. D.; Clements, Melanie; Al-Qassab, Hind; Heffron, Helen; Xu, Allison W.; Speakman, John R.; Barsh, Gregory S.; Viollet, Benoit; Vaulont, Sophie; Ashford, Michael L. J.; Carling, David; Withers, Dominic J.

In: The Journal of Clinical Investigation, Vol. 117, No. 8, 01.08.2007, p. 2325-2336.

Research output: Contribution to journalArticle

Claret, M, Smith, MA, Batterham, RL, Selman, C, Choudhury, AI, Fryer, LGD, Clements, M, Al-Qassab, H, Heffron, H, Xu, AW, Speakman, JR, Barsh, GS, Viollet, B, Vaulont, S, Ashford, MLJ, Carling, D & Withers, DJ 2007, 'AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons', The Journal of Clinical Investigation, vol. 117, no. 8, pp. 2325-2336. https://doi.org/10.1172/JCI31516
Claret, Marc ; Smith, Mark A. ; Batterham, Rachel L. ; Selman, Colin ; Choudhury, Agharul I. ; Fryer, Lee G. D. ; Clements, Melanie ; Al-Qassab, Hind ; Heffron, Helen ; Xu, Allison W. ; Speakman, John R. ; Barsh, Gregory S. ; Viollet, Benoit ; Vaulont, Sophie ; Ashford, Michael L. J. ; Carling, David ; Withers, Dominic J. / AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. In: The Journal of Clinical Investigation. 2007 ; Vol. 117, No. 8. pp. 2325-2336.
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AU - Smith, Mark A.

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AU - Selman, Colin

AU - Choudhury, Agharul I.

AU - Fryer, Lee G. D.

AU - Clements, Melanie

AU - Al-Qassab, Hind

AU - Heffron, Helen

AU - Xu, Allison W.

AU - Speakman, John R.

AU - Barsh, Gregory S.

AU - Viollet, Benoit

AU - Vaulont, Sophie

AU - Ashford, Michael L. J.

AU - Carling, David

AU - Withers, Dominic J.

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N2 - 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 POMC alpha 2KO and AgRP alpha 2KO mice lacking AMPK alpha 2 in proopiomelanocortin- (POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMC alpha 2KO 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 AMPK alpha 2-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 POMC alpha 2KO and AgRP alpha 2KO 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.

AB - 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 POMC alpha 2KO and AgRP alpha 2KO mice lacking AMPK alpha 2 in proopiomelanocortin- (POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMC alpha 2KO 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 AMPK alpha 2-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 POMC alpha 2KO and AgRP alpha 2KO 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.

KW - activated protein-kinase

KW - hypothalamic arcuate nucleus

KW - diabetes-obesity syndromes

KW - fatty-acid oxidation

KW - food-intake

KW - catalytic subunit

KW - upstream kinase

KW - skeletal-muscle

KW - nervous-system

KW - insulin

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JF - The Journal of Clinical Investigation

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