Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
J Neurochem. 2019 Apr;149(1):73-97. doi: 10.1111/jnc.14662. Epub 2019 Feb 11.
The hypothalamus is essential for regulation of energy homeostasis and metabolism. Feeding hypercaloric, high-fat (HF) diet induces hypothalamic arcuate nucleus injury and alters metabolism more severely in male than in female mice. The site(s) and extent of hypothalamic injury in male and female mice are not completely understood. In the paraventricular nucleus (PVN) of the hypothalamus, single-minded family basic helix-loop helix transcription factor 1 (Sim1) neurons are essential to control energy homeostasis. We tested the hypothesis that exposure to HF diet induces injury to Sim1 neurons in the PVN of male and female mice. Mice expressing membrane-bound enhanced green fluorescent protein (mEGFP) in Sim1 neurons (Sim1-Cre:Rosa-mEGFP mice) were generated to visualize the effects of exposure to HF diet on these neurons. Male and female Sim1-Cre:Rosa-mEGFP mice exposed to HF diet had increased weight, hyperleptinemia, and developed hepatosteatosis. In male and female mice exposed to HF diet, expression of mEGFP was reduced by > 40% in Sim1 neurons of the PVN, an effect paralleled by cell apoptosis and neuronal loss, but not by microgliosis. In the arcuate nucleus of the Sim1-Cre:Rosa-mEGFP male mice, there was decreased alpha-melanocyte-stimulating hormone in proopiomelanocortin neurons projecting to the PVN, with increased cell apoptosis, neuronal loss, and microgliosis. These defects were undetectable in the arcuate nucleus of female mice exposed to the HF diet. Thus, injury to Sim1 neurons of the PVN is a shared feature of exposure to HF diet in mice of both sexes, while injury to proopiomelanocortin neurons in arcuate nucleus is specific to male mice. OPEN SCIENCE BADGES: This article has received a badge for Open Materials because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
下丘脑对于能量平衡和代谢的调节至关重要。喂养高热量、高脂肪（HF）饮食会导致弓状核损伤，并使雄性小鼠的代谢改变比雌性更为严重。然而，雄性和雌性小鼠下丘脑损伤的部位和程度尚不完全清楚。在下丘脑的室旁核（PVN）中，单一导向家族基本螺旋-环-螺旋转录因子 1（Sim1）神经元对于控制能量平衡至关重要。我们假设 HF 饮食暴露会导致雄性和雌性小鼠 PVN 中的 Sim1 神经元损伤，并对此进行了测试。我们生成了表达膜结合增强型绿色荧光蛋白（mEGFP）的 Sim1 神经元（Sim1-Cre:Rosa-mEGFP 小鼠），以观察 HF 饮食暴露对这些神经元的影响。雄性和雌性 Sim1-Cre:Rosa-mEGFP 小鼠暴露于 HF 饮食后体重增加、瘦素水平升高，并发生肝脂肪变性。在雄性和雌性 HF 饮食暴露的小鼠中，PVN 中的 Sim1 神经元中 mEGFP 的表达减少了 >40%，这一效应伴随着细胞凋亡和神经元丢失，但不伴随着小胶质细胞增生。在雄性 Sim1-Cre:Rosa-mEGFP 小鼠的弓状核中，投射到 PVN 的前阿黑皮素原神经元中的α-黑色素细胞刺激素减少，同时伴随着细胞凋亡、神经元丢失和小胶质细胞增生。在雌性 HF 饮食暴露的小鼠的弓状核中，这些缺陷则无法检测到。因此，PVN 中的 Sim1 神经元损伤是雄性和雌性小鼠暴露于 HF 饮食的共同特征，而弓状核中的前阿黑皮素原神经元损伤则是雄性小鼠所特有的。开放科学徽章：本文因提供了重现研究所需的所有相关信息而获得了“开放材料”徽章。本文的完整开放科学披露表格可以在文章末尾找到。有关开放实践徽章的更多信息可以在 https://cos.io/our-services/open-science-badges/ 找到。
