PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response

Bengt F. Belgardt, Andreas Husch, Eva Rother, Marianne B. Ernst, F. Thomas Wunderlich, Brigitte Hampel, Tim Kloeckener, Dario Alessi, Peter Kloppenburg, Jens C. Bruening

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    Abstract

    Insulin- and leptin-stimulated phosphatidylinositol-3 kinase (PI3K) activation has been demonstrated to play a critical role in central control of energy homeostasis. To delineate the importance of pathways downstream of PI3K specifically in pro-opiomelanocortin (POMC) cell regulation, we have generated mice with selective inactivation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in POMC-expressing cells (PDK1(Delta POMC) mice). PDK1(Delta POMC) mice initially display hyperphagia, increased body weight, and impaired glucose metabolism caused by reduced hypothalamic POMC expression. On the other hand, PDK1(Delta POMC) mice exhibit progressive, severe hypocortisolism caused by loss of POW-expressing corti-cotrophs in the pituitary. Expression of a dominant-negative mutant of FOXO1 specifically in POW cells is sufficient to ameliorate positive energy balance in PDK1(Delta POMC) mice but cannot restore regular pituitary function. These results reveal important but differential roles for PDK1 signaling in hypothalamic and pituitary POMC cells in the control of energy homeostasis and stress response.

    Original languageEnglish
    Pages (from-to)291-301
    Number of pages11
    JournalCell Metabolism
    Volume7
    Issue number4
    DOIs
    Publication statusPublished - 2008

    Keywords

    • Humdisease
    • Molneuro
    • Signaling

    Cite this

    Belgardt, B. F., Husch, A., Rother, E., Ernst, M. B., Wunderlich, F. T., Hampel, B., Kloeckener, T., Alessi, D., Kloppenburg, P., & Bruening, J. C. (2008). PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell Metabolism, 7(4), 291-301. https://doi.org/10.1016/j.cmet.2008.01.006