The Role of Hypothalamic Slug in the Regulation of Leptin Sensitivity, Energy Balance, and Body Weight

摘要（说明） 肥胖与瘦素抵抗有关，这限制了瘦素治疗的潜力。瘦素抑制 食物摄入和增加能量消耗通过激活其受体（LepR）在下丘脑能量 平衡电路能量平衡回路的食物摄入臂已经被广泛地检查; 然而，对该电路的能量消耗臂知之甚少。此外，表观遗传重编程 下丘脑的能量消耗回路尚未在肥胖症的背景下进行探索。瘦素 刺激褐色和米色脂肪组织产热，促进能量消耗。布朗和 米色脂肪是维持啮齿类动物体温稳态所必需的，它们还保护 通过增加啮齿动物和人类的能量消耗来对抗肥胖。在初步研究中，我们 发现高脂饮食（HFD）喂养增加了下丘脑蛞蝓的水平，这是一种核表观遗传因子。我们 表明Slug诱导组蛋白3赖氨酸4（H3 K4）和H3 K9的甲基化和/或乙酰化， 表观遗传重塑的形式，在几个代谢基因启动子。我们发现鼻涕虫抑制了 表达Sh 2b 1，一种瘦素敏感性的正调节因子，并刺激SOCS 3，一种 瘦素信号的负调节因子。重要的是，小鼠中LepR+细胞特异性Slug缺失增加了LepR+的表达。 棕色和米色脂肪的交感神经支配，棕色/米色脂肪产热，能量消耗，以及 身体核心温度，但它不影响食物的摄入量。LepR+细胞特异性Slug敲除小鼠抵抗HFD- 诱导的瘦素抵抗、肥胖、胰岛素抵抗和肝脂肪变性。因此，我们假设，在 肥胖时，异常的下丘脑Slug通过一个神经元选择性地诱导能量消耗臂中的瘦素抵抗。 表观遗传机制选择性瘦素抵抗降低了温度设定点，这反过来又降低了 通过降低棕色/米色脂肪中的交感神经驱动来降低身体核心温度和能量消耗， 从而导致肥胖症的发展。我们将在三个目标中检验这些假设。目标1：确定 HFD喂养是否通过诱导下丘脑的表观遗传重编程诱导瘦素抵抗 Slug+LepR+电路通过Slug。目的2：确定HFD喂养是否损害瘦素/温度 设定点/SNS/棕色/米色脂肪途径通过表观遗传机制。目的3：确定表观遗传是否 瘦素/温度设定点/SNS/棕色/米色脂肪途径的调节引导能量消耗，身体 体重和新陈代谢。这个项目意义重大，因为它引入了表观遗传的新概念， 下丘脑能量平衡回路的重新编程和肥胖进展的调节 这一技术有望为肥胖症的治疗带来新的方法。

Abstract (Description) Obesity is associated with leptin resistance, which limits the potential of leptin therapies. Leptin suppresses food intake and increases energy expenditure by activating its receptors (LepR) in the hypothalamic energy balance circuitry. The food intake arm of the energy balance circuitry has been extensively examined; however, the energy expenditure arm of the circuitry is poorly understood. Moreover, epigenetic reprograming of the hypothalamic energy expenditure circuits has not been explored in the setting of obesity. Leptin stimulates brown and beige adipose tissue thermogenesis, contributing to energy expenditure. Brown and beige fat are required for the maintenance of body temperature homeostasis in rodents, and they also protect against obesity through increasing energy expenditure in both rodents and humans. In preliminary studies, we found that high fat diet (HFD) feeding increases the level of hypothalamic Slug, a nuclear epigenetic factor. We demonstrated that Slug induces methylations and/or acetylation of histone 3 lysine 4 (H3K4) and H3K9, key forms of epigenetic remodeling, in several metabolic gene promoters. We showed that Slug suppresses the expression of Sh2b1, a positive regulator of leptin sensitivity, and stimulates the expression of SOCS3, a negative regulator of leptin signaling. Importantly, LepR+ cell-specific deletion of Slug in mice increases the sympathetic innervation of brown and beige fat, brown/beige fat thermogenesis, energy expenditure, and the body core temperature, but it does not affect food intake. LepR+ cell-specific Slug knockout mice resist HFD- induced leptin resistance, obesity, insulin resistance, and liver steatosis. Hence, we hypothesize that in obesity, aberrant hypothalamic Slug induces leptin resistance selectively in the energy expenditure arm by an epigenetic mechanism. Selective leptin resistance lowers the temperature setpoint, which in turn decreases the body core temperature and energy expenditure through lowering the sympathetic drive in brown/beige fat, thereby contributing to obesity progression. We will test these hypotheses in 3 Aims. Aim 1: Determine whether HFD feeding induces leptin resistance by inducing epigenetic reprograming of the hypothalamic Slug+LepR+ circuits via Slug. Aim 2: Determine whether HFD feeding impairs the leptin/temperature setpoint/SNS/brown/beige fat pathway by epigenetic mechanisms. Aim 3: Determine whether epigenetic regulation of the leptin/temperature setpoint/SNS/brown/beige fat pathway guides energy expenditure, body weight, and metabolism. This project is significant because it introduces the novel concepts of epigenetic reprograming of the hypothalamic energy balance circuits and regulation of obesity progression by the temperature setpoint and is expected to lead to new approaches in therapies targeting obesity.