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Science 22 September 2000:
Vol. 289. no. 5487, pp. 2122 - 2125
DOI: 10.1126/science.289.5487.2122
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Reports

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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S. J. Fisher, J. C. Bruning, S. Lannon, and C. R. Kahn (2005)
Diabetes 54, 1447-1451
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Insulin Receptor Substrate 2 Plays Diverse Cell-specific Roles in the Regulation of Glucose Transport.
M. Sadagurski, G. Weingarten, C. J. Rhodes, M. F. White, and E. Wertheimer (2005)
J. Biol. Chem. 280, 14536-14544
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Reduced anorexic effects of insulin in obesity-prone rats fed a moderate-fat diet.
D. J. Clegg, S. C. Benoit, J. A. Reed, S. C. Woods, A. Dunn-Meynell, and B. E. Levin (2005)
Am J Physiol Regulatory Integrative Comp Physiol 288, R981-R986
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The Gut and Energy Balance: Visceral Allies in the Obesity Wars.
M. K. Badman and J. S. Flier (2005)
Science 307, 1909-1914
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Authors' Response: Frequent Occurrence of Hypogonadotropic Hypogonadism in Type 2 Diabetes.
S. Dhindsa, S. Prabhakar, and P. Dandona (2005)
J. Clin. Endocrinol. Metab. 90, 1903
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Western Diet Modulates Insulin Signaling, c-Jun N-Terminal Kinase Activity, and Insulin Receptor Substrate-1ser307 Phosphorylation in a Tissue-Specific Fashion.
P. O. Prada, H. G. Zecchin, A. L. Gasparetti, M. A. Torsoni, M. Ueno, A. E. Hirata, M. E. Corezola do Amaral, N. F. Hoer, A. C. Boschero, and M. J. A. Saad (2005)
Endocrinology 146, 1576-1587
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Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands.
S. J. Broughton, M. D. W. Piper, T. Ikeya, T. M. Bass, J. Jacobson, Y. Driege, P. Martinez, E. Hafen, D. J. Withers, S. J. Leevers, et al. (2005)
PNAS 102, 3105-3110
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Acute leptin deficiency, leptin resistance, and the physiologic response to leptin withdrawal.
J. M. Montez, A. Soukas, E. Asilmaz, G. Fayzikhodjaeva, G. Fantuzzi, and J. M. Friedman (2005)
PNAS 102, 2537-2542
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Insulin Receptor Substrate 2 Is Essential for Maturation and Survival of Photoreceptor Cells.
X. Yi, M. Schubert, N. S. Peachey, K. Suzuma, D. J. Burks, J. A. Kushner, I. Suzuma, C. Cahill, C. L. Flint, M. A. Dow, et al. (2005)
J. Neurosci. 25, 1240-1248
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Appetite control.
K. Wynne, S. Stanley, B. McGowan, and S. Bloom (2005)
J. Endocrinol. 184, 291-318
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Endocrine Control of Body Composition in Infancy, Childhood, and Puberty.
J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers (2005)
Endocr. Rev. 26, 114-146
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Diabetes, Obesity, and the Brain.
M. W. Schwartz and D. Porte Jr. (2005)
Science 307, 375-379
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Coordinated Regulation of Insulin Signaling by the Protein Tyrosine Phosphatases PTP1B and TCPTP.
S. Galic, C. Hauser, B. B. Kahn, F. G. Haj, B. G. Neel, N. K. Tonks, and T. Tiganis (2005)
Mol. Cell. Biol. 25, 819-829
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Adiposity Signaling and Biological Defense Against Weight Gain: Absence of Protection or Central Hormone Resistance?.
M. W. Schwartz and K. D. Niswender (2004)
J. Clin. Endocrinol. Metab. 89, 5889-5897
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Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism.
E. E. Zhang, E. Chapeau, K. Hagihara, and G.-S. Feng (2004)
PNAS 101, 16064-16069
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Frequent Occurrence of Hypogonadotropic Hypogonadism in Type 2 Diabetes.
S. Dhindsa, S. Prabhakar, M. Sethi, A. Bandyopadhyay, A. Chaudhuri, and P. Dandona (2004)
J. Clin. Endocrinol. Metab. 89, 5462-5468
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