TY - JOUR
T1 - Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons
AU - Vong, Linh
AU - Ye, Chianping
AU - Yang, Zongfang
AU - Choi, Brian
AU - Chua, Streamson
AU - Lowell, Bradford B.
N1 - Funding Information:
We would like to thank members of the Lowell laboratory for helpful discussions; C.B. Saper, C. Bjorbaek, and B.P. Bean for advice; J.K. Elmquist and D.P. Olson for comments on the manuscript; and M. Herman for help with statistics. This work was supported by grants from the National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK089044, R01 DK075632, P30 DK046200, and P30 DK057521 to B.B.L; PO1DK26687 and U54HD058155 to S.C.; F32 DK078478 to L.V.).
PY - 2011/7/14
Y1 - 2011/7/14
N2 - Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part because of incomplete knowledge regarding first-order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first-order neurons. While functionally relevant neurons have been identified, the observed effects have been small, suggesting that most first-order neurons remain unidentified. Here we take an alternative approach and test whether first-order neurons are inhibitory (GABAergic, VGAT+) or excitatory (glutamatergic, VGLUT2+). Remarkably, the vast majority of leptin's antiobesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons probably mediates, at least in part, leptin's antiobesity effects.
AB - Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part because of incomplete knowledge regarding first-order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first-order neurons. While functionally relevant neurons have been identified, the observed effects have been small, suggesting that most first-order neurons remain unidentified. Here we take an alternative approach and test whether first-order neurons are inhibitory (GABAergic, VGAT+) or excitatory (glutamatergic, VGLUT2+). Remarkably, the vast majority of leptin's antiobesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons probably mediates, at least in part, leptin's antiobesity effects.
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U2 - 10.1016/j.neuron.2011.05.028
DO - 10.1016/j.neuron.2011.05.028
M3 - Article
C2 - 21745644
AN - SCOPUS:79960190012
SN - 0896-6273
VL - 71
SP - 142
EP - 154
JO - Neuron
JF - Neuron
IS - 1
ER -