Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, 75390-9077, USA.
Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, 75390-9077, USA.
Mol Metab. 2020 May;35:100956. doi: 10.1016/j.molmet.2020.01.020. Epub 2020 Feb 4.
Histaminergic neurons of the tuberomammillary nucleus (TMN) are wake-promoting and contribute to the regulation of energy homeostasis. Evidence indicates that melanocortin 4 receptors (MC4R) are expressed within the TMN. However, whether the melanocortin system influences the activity and function of TMN neurons expressing histidine decarboxylase (HDC), the enzyme required for histamine synthesis, remains undefined.
We utilized Hdc-Cre mice in combination with whole-cell patch-clamp electrophysiology and in vivo chemogenetic techniques to determine whether HDC neurons receive metabolically relevant information via the melanocortin system.
We found that subsets of HDC-expressing neurons were excited by melanotan II (MTII), a non-selective melanocortin receptor agonist. Use of melanocortin receptor selective agonists (THIQ, [D-Trp]-γ-MSH) and inhibitors of synaptic transmission (TTX, CNQX, AP5) indicated that the effect was mediated specifically by MC4Rs and involved a glutamatergic dependent presynaptic mechanism. MTII enhanced evoked excitatory post-synaptic currents (EPSCs) originating from electrical stimulation of the perifornical lateral hypothalamic area (PeFLH), supportive of melanocortin effects on the glutamatergic PeFLH projection to the TMN. Finally, in vivo chemogenetic inhibition of HDC neurons strikingly enhanced the anorexigenic effects of intracerebroventricular administration of MTII, suggesting that MC4R activation of histaminergic neurons may restrain the anorexigenic effects of melanocortin system activation.
These experiments identify a functional interaction between the melanocortin and histaminergic systems and suggest that HDC neurons act naturally to restrain the anorexigenic effect of melanocortin system activation. These findings may have implications for the control of arousal and metabolic homeostasis, especially in the context of obesity, in which both processes are subjected to alterations.
结节乳头核（TMN）中的组胺能神经元具有促醒作用，并有助于调节能量稳态。有证据表明，黑皮质素 4 受体（MC4R）在 TMN 中表达。然而，黑皮质素系统是否会影响表达组氨酸脱羧酶（HDC）的 TMN 神经元的活性和功能，而 HDC 是合成组胺所必需的酶，目前仍不清楚。
我们利用 Hdc-Cre 小鼠结合全细胞膜片钳电生理学和体内化学遗传学技术，来确定 HDC 神经元是否通过黑皮质素系统接收与代谢相关的信息。
我们发现，HDC 表达神经元的亚群被黑素瘤促激素 II（MTII）兴奋，MTII 是一种非选择性黑皮质素受体激动剂。使用黑皮质素受体选择性激动剂（THIQ、[D-Trp]-γ-MSH）和突触传递抑制剂（TTX、CNQX、AP5）表明，这种作用是由 MC4R 介导的，涉及到谷氨酸能依赖的突触前机制。MTII 增强了电刺激peri-fornical lateral hypothalamic area（PeFLH）引起的兴奋性突触后电流（EPSC），支持黑皮质素对 TMN 的谷氨酸能 PeFLH 投射的作用。最后，体内化学遗传抑制 HDC 神经元显著增强了脑室注射 MTII 的厌食作用，表明 MC4R 对组胺能神经元的激活可能抑制了黑皮质素系统激活的厌食作用。
这些实验确定了黑皮质素和组胺能系统之间的功能相互作用，并表明 HDC 神经元自然地作用于抑制黑皮质素系统激活的厌食作用。这些发现可能对觉醒和代谢稳态的控制具有重要意义，尤其是在肥胖的情况下，这两个过程都受到影响。
