☆ 4.4 Article

Loss of Leptin Receptors on Hypothalamic POMC Neurons Alters Synaptic Inhibition

JOURNAL OF NEUROPHYSIOLOGY (2010)

Journal

JOURNAL OF NEUROPHYSIOLOGY

Volume 104, Issue 5, Pages 2321-2328

Publisher

AMER PHYSIOLOGICAL SOC

DOI: 10.1152/jn.00371.2010

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Funding

AECOM DRTC [P60 DK020541]
American Diabetes Association

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Abstract

Chun SK, Jo YH. Loss of leptin receptors on hypothalamic POMC neurons alters synaptic inhibition. J Neurophysiol 104: 2321-2328, 2010. First published September 15, 2010; doi:10.1152/jn.00371.2010. Adaptive changes in hypothalamic neural circuitry occur in response to alterations in nutritional status. This plasticity at hypothalamic synapses contributes to the control of food intake and body weight. Here we show that genetic ablation of leptin receptor gene expression in proopiomelanocortin (POMC) neurons (POMC: Lepr(-/-) GFP) induces alterations at synapses on POMC neurons in the arcuate nucleus of the hypothalamus. Our studies reveal that POMC: Lepr(-/-) GFP mice have decreased frequency of spontaneous GABAergic, but not glutamatergic, postsynaptic currents at synapses on POMC neurons. The decay time course of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) onto POMC neurons in POMC: Lepr(-/-) GFP mice is significantly slower than that of sIPSCs in control animals. While analysis of individual miniature IPSCs shows lowered baseline activity, this tonic decrease is associated with an increased amplitude and slow decay of mini-IPSCs onto POMC neurons in POMC: Lepr(-/-) GFP mice. Moreover, POMC neurons receive greater total ionic flux per GABAergic event in the absence of leptin receptor signaling. In addition, treatment with the alpha 3 subunit-containing GABA(A) receptor modulator SB-205384 enhances GABAergic transmission only onto POMC neurons in POMC: Lepr(-/-) GFP mice. Single-cell RT-PCR analysis further supports the expression of the alpha 3 subunit of the GABA(A) receptor on POMC neurons in POMC: Lepr(-/-) GFP mice. Finally, the responses to the GABA(A) receptor agonist isoguvacine of POMC neurons are significantly smaller in POMC: Lepr(-/-) GFP than in control animals. Therefore our present work demonstrates that loss of leptin signaling in POMC neurons induces synaptic alterations at POMC synapses that may play an essential role in energy homeostasis.

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Tumor-derived semaphorin 3D promoting cancer cachexia via regulating hypothalamic pro-opiomelanocortin neurons

Yanni Zhang, Qiulei Xi, Ming Zhong, Yi Jiang, Qiulin Zhuang, Zuoyou Ding, Shanjun Tan, Junjie Wang, Hao Liu, Zhige Zhang, Ben Zhou, Guohao Wu

Summary: Cachexia is common in cancer patients and its molecular basis is still unclear. This study investigated the regulatory pathway of tumors on appetite-inhibiting neurons (POMC) in the hypothalamus. Results showed that the tumor-expressed SEMA3D is positively related to POMC expression. Knocking out SEMA3D in mice increased food intake and body weight, and reduced muscle and fat catabolism. SEMA3D enhances POMC neuron activity by activating NRP2 and PlxnD1 expression. This research reveals that SEMA3D may play a vital role in appetite suppression and catabolic metabolism.

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