Dominant role of the p110β isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons

Hind Al-Qassab, Mark A Smith, Elaine E Irvine, Julie Guillermet-Guibert, Marc Claret, Agharul I Choudhury, Colin Selman, Kaisa Piipari, Melanie Clements, Steven Lingard, Keval Chandarana, Jimmy D Bell, Gregory S Barsh, Andrew J H Smith, Rachel L Batterham, Michael L J Ashford, Bart Vanhaesebroeck, Dominic J Withers

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Abstract

PI3K signaling is thought to mediate leptin and insulin action in hypothalamic pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, through largely unknown mechanisms. We inactivated either p110alpha or p110beta PI3K catalytic subunits in these neurons and demonstrate a dominant role for the latter in energy homeostasis regulation. In POMC neurons, p110beta inactivation prevented insulin- and leptin-stimulated electrophysiological responses. POMCp110beta null mice exhibited central leptin resistance, increased adiposity, and diet-induced obesity. In contrast, the response to leptin was not blocked in p110alpha-deficient POMC neurons. Accordingly, POMCp110alpha null mice displayed minimal energy homeostasis abnormalities. Similarly, in AgRP neurons, p110beta had a more important role than p110alpha. AgRPp110alpha null mice displayed normal energy homeostasis regulation, whereas AgRPp110beta null mice were lean, with increased leptin sensitivity and resistance to diet-induced obesity. These results demonstrate distinct metabolic roles for the p110alpha and p110beta isoforms of PI3K in hypothalamic energy regulation.
Original languageEnglish
Pages (from-to)343-354
Number of pages12
JournalCell Metabolism
Volume10
Issue number5
DOIs
Publication statusPublished - 4 Nov 2009

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Agouti-Related Protein
Pro-Opiomelanocortin
Leptin
Phosphatidylinositol 3-Kinases
Protein Isoforms
Homeostasis
Neurons
Obesity
Insulin
Diet
Adiposity
Catalytic Domain

Keywords

  • humdisease

Cite this

Al-Qassab, H., Smith, M. A., Irvine, E. E., Guillermet-Guibert, J., Claret, M., Choudhury, A. I., ... Withers, D. J. (2009). Dominant role of the p110β isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metabolism, 10(5), 343-354. https://doi.org/10.1016/j.cmet.2009.09.008

Dominant role of the p110β isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. / Al-Qassab, Hind; Smith, Mark A; Irvine, Elaine E; Guillermet-Guibert, Julie; Claret, Marc; Choudhury, Agharul I; Selman, Colin; Piipari, Kaisa; Clements, Melanie; Lingard, Steven; Chandarana, Keval; Bell, Jimmy D; Barsh, Gregory S; Smith, Andrew J H; Batterham, Rachel L; Ashford, Michael L J; Vanhaesebroeck, Bart; Withers, Dominic J.

In: Cell Metabolism, Vol. 10, No. 5, 04.11.2009, p. 343-354.

Research output: Contribution to journalArticle

Al-Qassab, H, Smith, MA, Irvine, EE, Guillermet-Guibert, J, Claret, M, Choudhury, AI, Selman, C, Piipari, K, Clements, M, Lingard, S, Chandarana, K, Bell, JD, Barsh, GS, Smith, AJH, Batterham, RL, Ashford, MLJ, Vanhaesebroeck, B & Withers, DJ 2009, 'Dominant role of the p110β isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons', Cell Metabolism, vol. 10, no. 5, pp. 343-354. https://doi.org/10.1016/j.cmet.2009.09.008
Al-Qassab H, Smith MA, Irvine EE, Guillermet-Guibert J, Claret M, Choudhury AI et al. Dominant role of the p110β isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metabolism. 2009 Nov 4;10(5):343-354. https://doi.org/10.1016/j.cmet.2009.09.008
Al-Qassab, Hind ; Smith, Mark A ; Irvine, Elaine E ; Guillermet-Guibert, Julie ; Claret, Marc ; Choudhury, Agharul I ; Selman, Colin ; Piipari, Kaisa ; Clements, Melanie ; Lingard, Steven ; Chandarana, Keval ; Bell, Jimmy D ; Barsh, Gregory S ; Smith, Andrew J H ; Batterham, Rachel L ; Ashford, Michael L J ; Vanhaesebroeck, Bart ; Withers, Dominic J. / Dominant role of the p110β isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. In: Cell Metabolism. 2009 ; Vol. 10, No. 5. pp. 343-354.
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AU - Claret, Marc

AU - Choudhury, Agharul I

AU - Selman, Colin

AU - Piipari, Kaisa

AU - Clements, Melanie

AU - Lingard, Steven

AU - Chandarana, Keval

AU - Bell, Jimmy D

AU - Barsh, Gregory S

AU - Smith, Andrew J H

AU - Batterham, Rachel L

AU - Ashford, Michael L J

AU - Vanhaesebroeck, Bart

AU - Withers, Dominic J

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N2 - PI3K signaling is thought to mediate leptin and insulin action in hypothalamic pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, through largely unknown mechanisms. We inactivated either p110alpha or p110beta PI3K catalytic subunits in these neurons and demonstrate a dominant role for the latter in energy homeostasis regulation. In POMC neurons, p110beta inactivation prevented insulin- and leptin-stimulated electrophysiological responses. POMCp110beta null mice exhibited central leptin resistance, increased adiposity, and diet-induced obesity. In contrast, the response to leptin was not blocked in p110alpha-deficient POMC neurons. Accordingly, POMCp110alpha null mice displayed minimal energy homeostasis abnormalities. Similarly, in AgRP neurons, p110beta had a more important role than p110alpha. AgRPp110alpha null mice displayed normal energy homeostasis regulation, whereas AgRPp110beta null mice were lean, with increased leptin sensitivity and resistance to diet-induced obesity. These results demonstrate distinct metabolic roles for the p110alpha and p110beta isoforms of PI3K in hypothalamic energy regulation.

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