Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice

Marc Claret, Mark A. Smith, Claude Knauf, Hind Al-Qassab, Angela Woods, Amanda Heslegrave, Kaisa Piipari, Julian J. Emmanuel, Andre Colom, Philippe Valet, Patrice D. Cani, Ghazala Begum, Anne White, Phillip Mucket, Marco Peters, Keiko Mizuno, Rachel L. Batterham, K. Peter Giese, Alan Ashworth, Remy Burcelin & 3 others Michael L. Ashford, David Carling, Dominic J. Withers

    Research output: Contribution to journalArticle

    30 Citations (Scopus)

    Abstract

    OBJECTIVE AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampk alpha 2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+-calmodulin-dependent protein kinase kinase beta (CaMKK beta) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation.

    RESEARCH DESIGN AND METHODS Mice lacking either Camkk beta or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.

    RESULTS Deletion of Camkk beta in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased alpha-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice.

    CONCLUSIONS Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons. Diabetes 60:735-745, 2011

    Original languageEnglish
    Pages (from-to)735-745
    Number of pages11
    JournalDiabetes
    Volume60
    Issue number3
    DOIs
    Publication statusPublished - Mar 2011

    Keywords

    • ACTIVATED PROTEIN-KINASE
    • INCREASES INSULIN SENSITIVITY
    • HEPATIC GLUCOSE
    • MELANOCORTIN PATHWAYS
    • RECEPTOR SUBSTRATE-2
    • UPSTREAM KINASE
    • ARCUATE NUCLEUS
    • AGRP NEURONS
    • SAD KINASES
    • FOOD-INTAKE

    Cite this

    Claret, M., Smith, M. A., Knauf, C., Al-Qassab, H., Woods, A., Heslegrave, A., ... Withers, D. J. (2011). Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice. Diabetes, 60(3), 735-745. https://doi.org/10.2337/db10-1055
    Claret, Marc ; Smith, Mark A. ; Knauf, Claude ; Al-Qassab, Hind ; Woods, Angela ; Heslegrave, Amanda ; Piipari, Kaisa ; Emmanuel, Julian J. ; Colom, Andre ; Valet, Philippe ; Cani, Patrice D. ; Begum, Ghazala ; White, Anne ; Mucket, Phillip ; Peters, Marco ; Mizuno, Keiko ; Batterham, Rachel L. ; Giese, K. Peter ; Ashworth, Alan ; Burcelin, Remy ; Ashford, Michael L. ; Carling, David ; Withers, Dominic J. / Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice. In: Diabetes. 2011 ; Vol. 60, No. 3. pp. 735-745.
    @article{228e9547087348469e86e271fc6a319b,
    title = "Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice",
    abstract = "OBJECTIVE AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampk alpha 2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+-calmodulin-dependent protein kinase kinase beta (CaMKK beta) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation.RESEARCH DESIGN AND METHODS Mice lacking either Camkk beta or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.RESULTS Deletion of Camkk beta in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased alpha-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice.CONCLUSIONS Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons. Diabetes 60:735-745, 2011",
    keywords = "ACTIVATED PROTEIN-KINASE, INCREASES INSULIN SENSITIVITY, HEPATIC GLUCOSE, MELANOCORTIN PATHWAYS, RECEPTOR SUBSTRATE-2, UPSTREAM KINASE, ARCUATE NUCLEUS, AGRP NEURONS, SAD KINASES, FOOD-INTAKE",
    author = "Marc Claret and Smith, {Mark A.} and Claude Knauf and Hind Al-Qassab and Angela Woods and Amanda Heslegrave and Kaisa Piipari and Emmanuel, {Julian J.} and Andre Colom and Philippe Valet and Cani, {Patrice D.} and Ghazala Begum and Anne White and Phillip Mucket and Marco Peters and Keiko Mizuno and Batterham, {Rachel L.} and Giese, {K. Peter} and Alan Ashworth and Remy Burcelin and Ashford, {Michael L.} and David Carling and Withers, {Dominic J.}",
    year = "2011",
    month = "3",
    doi = "10.2337/db10-1055",
    language = "English",
    volume = "60",
    pages = "735--745",
    journal = "Diabetes",
    issn = "0012-1797",
    publisher = "American Diabetes Association",
    number = "3",

    }

    Claret, M, Smith, MA, Knauf, C, Al-Qassab, H, Woods, A, Heslegrave, A, Piipari, K, Emmanuel, JJ, Colom, A, Valet, P, Cani, PD, Begum, G, White, A, Mucket, P, Peters, M, Mizuno, K, Batterham, RL, Giese, KP, Ashworth, A, Burcelin, R, Ashford, ML, Carling, D & Withers, DJ 2011, 'Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice', Diabetes, vol. 60, no. 3, pp. 735-745. https://doi.org/10.2337/db10-1055

    Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice. / Claret, Marc; Smith, Mark A.; Knauf, Claude; Al-Qassab, Hind; Woods, Angela; Heslegrave, Amanda; Piipari, Kaisa; Emmanuel, Julian J.; Colom, Andre; Valet, Philippe; Cani, Patrice D.; Begum, Ghazala; White, Anne; Mucket, Phillip; Peters, Marco; Mizuno, Keiko; Batterham, Rachel L.; Giese, K. Peter; Ashworth, Alan; Burcelin, Remy; Ashford, Michael L.; Carling, David; Withers, Dominic J.

    In: Diabetes, Vol. 60, No. 3, 03.2011, p. 735-745.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice

    AU - Claret, Marc

    AU - Smith, Mark A.

    AU - Knauf, Claude

    AU - Al-Qassab, Hind

    AU - Woods, Angela

    AU - Heslegrave, Amanda

    AU - Piipari, Kaisa

    AU - Emmanuel, Julian J.

    AU - Colom, Andre

    AU - Valet, Philippe

    AU - Cani, Patrice D.

    AU - Begum, Ghazala

    AU - White, Anne

    AU - Mucket, Phillip

    AU - Peters, Marco

    AU - Mizuno, Keiko

    AU - Batterham, Rachel L.

    AU - Giese, K. Peter

    AU - Ashworth, Alan

    AU - Burcelin, Remy

    AU - Ashford, Michael L.

    AU - Carling, David

    AU - Withers, Dominic J.

    PY - 2011/3

    Y1 - 2011/3

    N2 - OBJECTIVE AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampk alpha 2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+-calmodulin-dependent protein kinase kinase beta (CaMKK beta) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation.RESEARCH DESIGN AND METHODS Mice lacking either Camkk beta or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.RESULTS Deletion of Camkk beta in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased alpha-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice.CONCLUSIONS Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons. Diabetes 60:735-745, 2011

    AB - OBJECTIVE AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampk alpha 2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+-calmodulin-dependent protein kinase kinase beta (CaMKK beta) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation.RESEARCH DESIGN AND METHODS Mice lacking either Camkk beta or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.RESULTS Deletion of Camkk beta in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased alpha-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice.CONCLUSIONS Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons. Diabetes 60:735-745, 2011

    KW - ACTIVATED PROTEIN-KINASE

    KW - INCREASES INSULIN SENSITIVITY

    KW - HEPATIC GLUCOSE

    KW - MELANOCORTIN PATHWAYS

    KW - RECEPTOR SUBSTRATE-2

    KW - UPSTREAM KINASE

    KW - ARCUATE NUCLEUS

    KW - AGRP NEURONS

    KW - SAD KINASES

    KW - FOOD-INTAKE

    U2 - 10.2337/db10-1055

    DO - 10.2337/db10-1055

    M3 - Article

    VL - 60

    SP - 735

    EP - 745

    JO - Diabetes

    JF - Diabetes

    SN - 0012-1797

    IS - 3

    ER -

    Claret M, Smith MA, Knauf C, Al-Qassab H, Woods A, Heslegrave A et al. Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice. Diabetes. 2011 Mar;60(3):735-745. https://doi.org/10.2337/db10-1055