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Science 334 (6059): 1133-1137

Copyright © 2011 by the American Association for the Advancement of Science

Transplanted Hypothalamic Neurons Restore Leptin Signaling and Ameliorate Obesity in db/db Mice

Artur Czupryn,1,2,3,* Yu-Dong Zhou,4,*,{dagger} Xi Chen,5,* David McNay,5,{ddagger} Matthew P. Anderson,4,||, Jeffrey S. Flier,5,6,§,|| Jeffrey D. Macklis1,2,6,§,||

Abstract: Evolutionarily old and conserved homeostatic systems in the brain, including the hypothalamus, are organized into nuclear structures of heterogeneous and diverse neuron populations. To investigate whether such circuits can be functionally reconstituted by synaptic integration of similarly diverse populations of neurons, we generated physically chimeric hypothalami by microtransplanting small numbers of embryonic enhanced green fluorescent protein–expressing, leptin-responsive hypothalamic cells into hypothalami of postnatal leptin receptor–deficient (db/db) mice that develop morbid obesity. Donor neurons differentiated and integrated as four distinct hypothalamic neuron subtypes, formed functional excitatory and inhibitory synapses, partially restored leptin responsiveness, and ameliorated hyperglycemia and obesity in db/db mice. These experiments serve as a proof of concept that transplanted neurons can functionally reconstitute complex neuronal circuitry in the mammalian brain.

1 Department of Stem Cell and Regenerative Biology, and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
2 MGH-HMS Center for Nervous System Repair, Departments of Neurology and Neurosurgery, and Program in Neuroscience, Harvard Medical School; Nayef Al-Rodhan Laboratories, Massachusetts General Hospital, Boston, MA 02114, USA.
3 Nencki Institute of Experimental Biology, Department of Molecular and Cellular Neurobiology, Warsaw, 02-093, Poland.
4 Departments of Neurology and Pathology, and Program in Neuroscience, Harvard Medical School; Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
5 Beth Israel Deaconess Medical Center, Division of Endocrinology, Diabetes, and Metabolism, and Harvard Medical School, Boston, MA 02215, USA.
6 Harvard Medical School, Boston, MA 02215, USA.

* These authors contributed equally to this work.

{dagger} Present address: Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.

{ddagger} Present address: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB24 2TZ, Scotland, UK.

§ These authors contributed equally to this work.

||To whom correspondence should be addressed. E-mail: jeffrey_macklis{at} (J.D.M.); jeffrey_flier{at} (J.S.F.); matthew_anderson{at} (M.P.A.)

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