Department of Biomedical Sciences and Nutrient and Metabolite Sensing, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
J Neuroendocrinol. 2019 Jul;31(7):e12761. doi: 10.1111/jne.12761.
Dopamine-producing tyrosine hydroxylase (TH) neurones in the hypothalamic arcuate nucleus (ARC) have recently been shown to be involved in ghrelin signalling and body weight homeostasis. In the present study, we investigate the role of the intracellular regulator RhoA in hypothalamic TH neurones in response to peripheral hormones. Diet-induced obesity was found to be associated with increased phosphorylation of TH in ARC, indicating obesity-associated increased activity of ARC TH neurones. Mice in which RhoA was specifically knocked out in TH neurones (TH-RhoA mice) were more sensitive to the orexigenic effect of peripherally administered ghrelin and displayed an abolished response to the anorexigenic hormone leptin. When TH-RhoA mice were challenged with a high-fat high-sucrose (HFHS) diet, they became hyperphagic and gained more body weight and fat mass compared to wild-type control mice. Importantly, lack of RhoA prevented development of ghrelin resistance, which is normally observed in wild-type mice after long-term HFHS diet feeding. Patch-clamp electrophysiological analysis demonstrated increased ghrelin-induced excitability of TH neurones in lean TH-RhoA mice compared to lean littermate control animals. Additionally, increased expression of the orexigenic hypothalamic neuropeptides agouti-related peptide and neuropeptide Y was observed in TH-RhoA mice. Overall, our data indicate that TH neurones in ARC are important for the regulation of body weight homeostasis and that RhoA is both a central effector in these neurones and important for the development of obesity-induced ghrelin resistance. The obese phenotype of TH-RhoA mice may be a result of increased sensitivity to ghrelin and decreased sensitivity to leptin, resulting in increased food intake.
下丘脑弓状核（ARC）中产生多巴胺的酪氨酸羟化酶（TH）神经元最近被证明参与了胃饥饿素信号转导和体重稳态调节。在本研究中，我们研究了细胞内调节因子 RhoA 在响应外周激素的下丘脑 TH 神经元中的作用。研究发现，饮食诱导的肥胖与 ARC 中 TH 的磷酸化增加有关，这表明与肥胖相关的 ARC TH 神经元活性增加。在 TH 神经元中特异性敲除 RhoA 的小鼠（TH-RhoA 小鼠）对外周给予的胃饥饿素的摄食作用更为敏感，并且对厌食激素瘦素的反应被消除。当 TH-RhoA 小鼠接受高脂肪高蔗糖（HFHS）饮食挑战时，与野生型对照小鼠相比，它们变得过度摄食，体重和脂肪量增加更多。重要的是，缺乏 RhoA 可防止胃饥饿素抵抗的发展，而在野生型小鼠长期 HFHS 饮食喂养后通常会观察到这种抵抗。膜片钳电生理分析表明，与瘦型同窝对照动物相比，瘦型 TH-RhoA 小鼠中胃饥饿素诱导的 TH 神经元兴奋性增加。此外，在 TH-RhoA 小鼠中观察到食欲肽下丘脑神经肽 agouti 相关肽和神经肽 Y 的表达增加。总体而言，我们的数据表明，ARC 中的 TH 神经元对于调节体重稳态非常重要，并且 RhoA 既是这些神经元中的中央效应物，也是肥胖诱导的胃饥饿素抵抗发展的重要因素。TH-RhoA 小鼠的肥胖表型可能是由于对胃饥饿素的敏感性增加和对瘦素的敏感性降低，导致食物摄入量增加的结果。
