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

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 po...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2011-11, Vol.334 (6059), p.1133-1137
Main Authors: Czupryn, Artur, Zhou, Yu-Dong, Chen, Xi, McNay, David, Anderson, Matthew P., Flier, Jeffrey S., Macklis, Jeffrey D.
Format: Article
Language:English
Subjects:
Action potentials
Animals
Biological and medical sciences
Blood Glucose - analysis
Body Weight
Brain
Cell Shape
Cell transplantation
Donors
Electric current
Electrophysiological Phenomena
Excitatory Postsynaptic Potentials
Fundamental and applied biological sciences. Psychology
Glucose - administration & dosage
Hypothalamus
Hypothalamus - cytology
Hypothalamus - metabolism
Hypothalamus, Middle - cytology
Hypothalamus, Middle - metabolism
Hypothalamus, Middle - physiopathology
Inhibitory Postsynaptic Potentials
Insulin
Insulin - administration & dosage
Insulin - blood
Leptin - administration & dosage
Leptin - metabolism
Medical sciences
Membrane Potentials
Metabolic diseases
Mice
Mice, Obese
Neurogenesis
Neurons
Neurons - cytology
Neurons - physiology
Neurons - transplantation
Neuroscience
Obesity
Obesity - metabolism
Obesity - physiopathology
Obesity - therapy
Receptors, Leptin - metabolism
Signal Transduction
Synaptic Transmission
Vertebrates: nervous system and sense organs
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1209870