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

  1. Dominic J. Withers2
  1. 1Laboratory of Diabetes and Obesity, Endocrinology and Nutrition Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic de Barcelona, Barcelona, Spain
  2. 2Metabolic Signalling Group, Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, London, U.K.
  3. 3Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K.
  4. 4Institut National de la Santé et de la Recherche Médicale U858, Institut de Médecine Moléculaire de Rangueil, Toulouse, France
  5. 5Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College London, London, U.K.
  6. 6Centre for Diabetes and Endocrinology, Rayne Institute, University College London, London, U.K.
  7. 7Louvain Drug Research Institute, Unit of Pharmacokinetics, Metabolism, Nutrition, and Toxicology, Université Catholique de Louvain, Brussels, Belgium
  8. 8Faculties of Life Sciences and Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, U.K.
  9. 9Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King’s College London, London, U.K.
  10. 10The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, U.K.
  1. Corresponding author: Dominic J. Withers, d.withers{at}, or Marc Claret, mclaret{at}


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 Ampkα2 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 β (CaMKKβ) 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 Camkkβ or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.

RESULTS Deletion of Camkkβ 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 α-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.


  • Received July 27, 2010.
  • Accepted December 14, 2010.

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  1. Diabetes vol. 60 no. 3 735-745
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