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Science 289 (5487): 2122-2125

Copyright © 2000 by the American Association for the Advancement of Science

Role of Brain Insulin Receptor in Control of Body Weight and Reproduction

Jens C. Brüning,1* Dinesh Gautam,1 Deborah J. Burks,2 Jennifer Gillette,1 Markus Schubert,1 Paul C. Orban,3dagger Rüdiger Klein,3 Wilhelm Krone,1 Dirk Müller-Wieland,1 C. Ronald Kahn2*

Insulin receptors (IRs) and insulin signaling proteins are widely distributed throughout the central nervous system (CNS). To study the physiological role of insulin signaling in the brain, we created mice with a neuron-specific disruption of the IR gene (NIRKO mice). Inactivation of the IR had no impact on brain development or neuronal survival. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of luteinizing hormone. Thus, IR signaling in the CNS plays an important role in regulation of energy disposal, fuel metabolism, and reproduction.

1 Klinik II und Poliklinik für Innere Medizin and Center of Molecular Medicine (ZMMK) der Universität zu Köln, Joseph Stelzmann Strasse 9, 50931 Cologne, Germany.
2 Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
3 European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
*   To whom correspondence should be addressed. E-mail: jens.bruening{at}uni-koeln.de and c.ronald.kahn{at}joslin.harvard.edu

dagger    Present address: San Raffaele Scientific Institute, DIBIT-HSR, Olgettina 60, Milan, Italy.

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Developmental Programming: Excess Weight Gain Amplifies the Effects of Prenatal Testosterone Excess On Reproductive Cyclicity--Implication for Polycystic Ovary Syndrome.
T. L. Steckler, C. Herkimer, D. A. Dumesic, and V. Padmanabhan (2009)
Endocrinology 150, 1456-1465
   Abstract »    Full Text »    PDF »
Insulin, leptin, and food reward: update 2008.
D. P. Figlewicz and S. C. Benoit (2009)
Am J Physiol Regulatory Integrative Comp Physiol 296, R9-R19
   Abstract »    Full Text »    PDF »
Hyperleptinaemia rather than fasting hyperinsulinaemia is associated with obesity following hypothalamic damage in children.
M G. Shaikh, R. G Grundy, and J. M W Kirk (2008)
Eur. J. Endocrinol. 159, 791-797
   Abstract »    Full Text »    PDF »
Fasting-induced suppression of LH secretion does not require activation of ATP-sensitive potassium channels.
W. Huang, M. Acosta-Martinez, T. H. Horton, and J. E. Levine (2008)
Am J Physiol Endocrinol Metab 295, E1439-E1446
   Abstract »    Full Text »    PDF »
Hypothalamic Malonyl-Coenzyme A and the Control of Energy Balance.
M. J. Wolfgang and M. D. Lane (2008)
Mol. Endocrinol. 22, 2012-2020
   Abstract »    Full Text »    PDF »
C. elegans dauer formation and the molecular basis of plasticity.
N. Fielenbach and A. Antebi (2008)
Genes & Dev. 22, 2149-2165
   Abstract »    Full Text »    PDF »
Loss of Neuroprotective Survival Signal in Mice Lacking Insulin Receptor Gene in Rod Photoreceptor Cells.
A. Rajala, M. Tanito, Y. Z. Le, C. R. Kahn, and R. V. S. Rajala (2008)
J. Biol. Chem. 283, 19781-19792
   Abstract »    Full Text »    PDF »
Starvation and Triglycerides Reverse the Obesity-Induced Impairment of Insulin Transport at the Blood-Brain Barrier.
A. Urayama and W. A. Banks (2008)
Endocrinology 149, 3592-3597
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A high-carbohydrate diet in the immediate postnatal life of rats induces adaptations predisposing to adult-onset obesity.
M. Srinivasan, P. Mitrani, G. Sadhanandan, C. Dodds, S. Shbeir-ElDika, S. Thamotharan, H. Ghanim, P. Dandona, S. U Devaskar, and M. S Patel (2008)
J. Endocrinol. 197, 565-574
   Abstract »    Full Text »    PDF »
Effects of Euglycemic Hyperinsulinemia and Lipid Infusion on Circulating Cholecystokinin.
M. O. Weickert, M. Mohlig, J. Spranger, C. Schofl, C. V. Loeffelholz, R. L. Riepl, B. Otto, and A. F. H. Pfeiffer (2008)
J. Clin. Endocrinol. Metab. 93, 2328-2333
   Abstract »    Full Text »    PDF »
Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice.
I. Lastres-Becker, S. Brodesser, D. Lutjohann, M. Azizov, J. Buchmann, E. Hintermann, K. Sandhoff, A. Schurmann, J. Nowock, and G. Auburger (2008)
Hum. Mol. Genet. 17, 1465-1481
   Abstract »    Full Text »    PDF »
Overview of human obesity and central mechanisms regulating energy homeostasis.
V. E. F. Crowley (2008)
Annals of Clinical Biochemistry 45, 245-255
   Abstract »    Full Text »    PDF »
Hyperandrogenism and Hyperinsulinism in Children of Women with Polycystic Ovary Syndrome: A Controlled Study.
S. C. Kent, C. L. Gnatuk, A. R. Kunselman, L. M. Demers, P. A. Lee, and R. S. Legro (2008)
J. Clin. Endocrinol. Metab. 93, 1662-1669
   Abstract »    Full Text »    PDF »

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