The role of hypothalamic estrogen receptors in metabolic regulation

Estrogens regulate key features of metabolism, including food intake, body weight, energy expenditure, insulin sensitivity, leptin sensitivity, and body fat distribution. There are two ‘classical’ estrogen receptors (ERs): estrogen receptor alpha (ERS1) and estrogen receptor beta (ERS2). Human and murine data indicate ERS1 contributes to metabolic regulation more so than ESR2. For example, there are human inactivating mutations of ERS1 which recapitulate aspects of the metabolic syndrome in both men and women. Much of our understanding of the metabolic roles of ERS1 was initially uncovered in estrogen receptor α-null mice (ERS1^−/−); these mice display aspects of the metabolic syndrome, including increased body weight, increased visceral fat deposition and dysregulated glucose intolerance. Recent data further implicate ERS1 in specific tissues and neuronal populations as being critical for regulating food intake, energy expenditure, body fat distribution and adipose tissue function. This review will focus predominantly on the role of hypothalamic ERs and their critical role in regulating all aspects of energy homeostasis and metabolism.     

Promotion of normal healing of bone defects under estrogen deficiency by implantation of beta‐tricalcium phosphate composed of rod‐shaped particles

We compared the healing of bone defects in ovariectomized rats implanted with beta‐tricalcium phosphate (β‐TCP) composed of rod‐shaped particles, which were prepared using the applied hydrothermal method (HTCP), and that of bone defects implanted with conventional β‐TCP composed of globular‐shaped particles (CTCP), which were prepared by normal sintering. Eight‐week‐old female Wistar rats were ovariectomized, and 2 weeks after the operation, 0.5‐ to 0.6‐mm diameter spherical granules of each ceramic were implanted in a bone defect created in the distal end of the femur. Four, 8, and 12 weeks after implantation, the amount of newly formed bone implanted with HTCP was significantly larger than that implanted with CTCP and was equivalent to that in non‐ovariectomized sham‐operated rats. Without implantation, spontaneous repair of the trabecular bone was barely observed. The physiological structure of the trabecular network was maintained in the region implanted with HTCP, but that in the region implanted with CTCP was severely destroyed. Gene expression microarray analysis revealed that the expression of genes involved in interferon signaling pathways was upregulated in osteoclasts cultured on HTCP compared with that cultured on CTCP. Our results suggest that the microstructure of β‐TCP affected the biological behavior of osteoclasts and regulated local bone metabolism. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:189–196, 2014.     

骨质疏松症动物模型研究进展

骨质疏松症(osteoporosis,OP)是一种临床上常见的以骨量减少和骨组织微观结构破坏为特点,从而导致骨脆性增加、易于发生骨折的全身代谢性疾病。随着人口老龄化进程的加速,骨质疏松症尤其是绝经后骨质疏松症的发生率逐渐上升,骨质疏松症在医学上和社会性的影响逐渐加深。人类骨质疏松症主要有糖皮质激素相关型、绝经后骨质疏松症以及失用型、老年性骨质疏松症几种类型。糖皮质激素相关型骨质疏松症动物模型利用糖皮质激素诱导建立,其降低成骨细胞的活性、刺激破骨细胞,从而减少骨形成、增加骨吸收。利用去势法建立绝经后骨质疏松动物模型,其原理是雌激素减少致使骨吸收增加、新骨形成降低,最终达到骨量减少的目的。雌激素受体α诱导破骨细胞凋亡,但是阻碍成骨细胞功能的机制目前尚不明确。SAM-P6(Senescence-accelerated mouse-P6)是一种衰老加速的小鼠,骨丢失随年龄增长而增加,适用于老年型骨质疏松动物模型。失用型骨质疏松动物模型常见的建模方法有坐骨神经切除法、悬吊法等,机体长期处于无重力负荷状态,使得破骨细胞活性相对增加,导致骨量丢失。笔者就不同种类动物作为骨质疏松症研究模型的优缺点、绝经后骨质疏松症动物模型中对不同部位骨骼的影响作简要概述。     

Possible antiosteoporotic mechanism of Cicer arietinum extract in ovariectomized rats

Objective: The present study aimed to throw the light on the anti-osteoprotic mechanism of Cicer arietinum extract (CAE) seeds against ovariectomized (OVX) rats. Methods: Seventy female rats were divided into two groups. The first group (14 rats/group) represented normal rats (Sham operated) while the second group (56 rats/group) underwent bilateral ovariectomy (OVX). After one week of recovery from ovariectomy surgery, the second group was randomly subdivided into 4 subgroups (14 rats/ each subgroup). The rats administered orally; distilled water (vehicle) (1^st subgroup), Cicer arietinum extract (CAE) (500 or 1000 mg/kg body weight/day) (2^nd and 3^rd subgroups), alendronate (6.5 mg/kg mg/kg body weight) as a positive control one time/week (4^rh subgroup), daily for 10 weeks. Results: The present study demonstrated that ovariectomy caused significant decrease in bone mineral; density (BMD) and content (BMC), Bone-specific alkaline phosphatase (BALP), calcium (Ca), phosphorus (P), parathyroid hormone (PTH) and calcitonin levels. Furthermore, ovariectomy induced significant elevation of tartrate-resistant acid phosphatase 5b (TRAP 5b) and receptor activator of nuclear factor (NF-kappa β) ligand (RANKL) concentration. Conversely, osteoprotegerin (OPG) and OPG/RANKL ratio were decreased following ovariectomy. The present work suggests that CAE has antiosteoporotic action against ovariectomy effects and its activity may results from its phytochemical and/or phytoestrogen contents. Conclusion: The ongoing study speculates that the CAE exerts its action through regulation of RANK/RANKL/OPG system. As, CAE not only promotes osteoblast differentiation, but also up-regulates OPG and downregulates RANKL secretion in osteoblasts, subsequently prevents bone loss and osteoporosis.     

盐酸帕罗西汀对卵巢切除大鼠学习记忆能力及血清雌激素水平的影响

目的：探讨抗抑郁剂盐酸帕罗西汀对卵巢切除大鼠学习记忆能力、血清雌激素水平及大鼠海马雌激素受体表达的影响。方法采用 SD 雌鼠双侧卵巢切除（OVX）作为雌激素波动引起的抑郁与认知障碍模型,用 Morris 水迷宫实验来测试大鼠的学习记忆功能。实验共分为正常对照组、OVX对照组、OVX 药物组。予5-羟色胺重摄取抑制剂类药物：盐酸帕罗西汀10 mg／（kg·d）干预4周。采用 ELISA 法测量SD 大鼠血清黄体生成素、卵泡刺激素、雌激素。免疫组化法检测大鼠海马雌激素受体α（ERα）和雌激素受体β（ERβ）的阳性细胞表达数。结果① Morris 水迷宫实验中,OVX对照组和 OVX 药物组的逃避潜伏期明显缩短,停留在平台时间百分比明显增加。② OVX 药物组的血清雌激素较OVX 对照组明显增加（P ＜0．05）。③药物组与非药物组的ERα、ERβ表达无明显差异。结论帕罗西汀增加OVX 大鼠血清雌激素水平和改善学习记忆能力,而对海马ERα、ERβ表达无明显影响。     

Ovariectomy shortens the life span of female mice

This study shows that lack of ovarian activity has a negative impact on the life span of female mice. The extent to which this phenomenon could be associated with the anti-inflammatory effect of estrogens was analyzed in metabolic organs and aorta, by quantitative analysis of mRNAs encoding proteins in the inflammatory cascade. We demonstrate that the TNFα, IL-1β, MCP-1, MIP-2 and IL-6 mRNA contents are increased in the liver, adipose tissue and aorta 7 months after ovariectomy (ovx) and this increased basal inflammation is maintained as the mice aged. In contrast, the extent of inflammatory gene expression is directly proportional to age in sham-operated mice. As a consequence, at 22 months, most of the inflammatory parameters examined were higher in the sham-operated group compared with the ovx group. These observations led us to propose that the decreased longevity of ovx mice may be due to an acceleration of the basal state of inflammation in metabolic organs, which is likely driven by the combination of a lack of estrogen-mediated anti-inflammatory activity and the loss of gonadal control of energy metabolism.     

Metformin ameliorates the age‐related changes of d‐galactose administration in ovariectomized mice

Metformin (Met) has been shown to have pleiotropic effects such as neuroprotective, antioxidant, and anti‐inflammatory properties making that a potential candidate for the treatment of central nervous system (CNS) disorders. This study was designed to investigate the possible effect of Met on the d ‐galactose (d ‐gal)‐induced aging in ovariectomized mice. The female mice underwent bilateral ovariectomy. d ‐gal was administered orally at a dose of 500 mg/kg, and Met was administrated orally at doses of 1 and 10 mg/kg for 6 weeks. Anxiety‐like behavior was evaluated by the elevated plus‐maze. Physical power was assessed by vertical grid holding test and forced swimming capacity test. The brains were assessed for the level of superoxide dismutase (SOD) and brain‐derived neurotrophic factor (BDNF). Ovariectomy caused anxiety and declined the physical power as well as BDNF and SOD levels. d ‐gal administration in ovariectomized mice exacerbated these deleterious effects. Met hampered the anxiety‐like behavior and strengthened the physical power of d ‐gal‐treated ovariectomized mice. Met also increased the SOD and BDNF levels in the brains of d ‐gal‐treated ovariectomized animals. Based on the obtained results, we suggest Met administration as a novel therapeutic approach for the treatment of age‐related conditions in the absence of female sex hormones.     

去势比格犬腹部脂肪与相关血清学指标及骨密度的变化关系

目的通过建立去势比格犬模型,观察绝经早期腹部脂肪变化规律,并通过对脂肪与骨代谢相关血清学指标的测量与分析,探讨脂肪及骨代谢的关键影响因素。方法选取6只成年雌性比格犬进行去势术,分别在术前、术后4个月、6个月、10个月进行腰椎定量CT(quantatitive computed tomography,QCT)腹部脂肪面积、骨密度(bone mineral density,BMD)、MRI腰椎骨髓脂肪含量及血清学指标的检测,比较不同时间各指标的变化趋势及关系。结果比格犬腹内脂肪面积(visceral fat area,VFA)、皮下脂肪面积(subcutaneous fat area,SFA)、腹部总脂肪面积(total fat area,TFA)在术后6个月、10个月均增加(P0.05),术后10个月VFA增加百分比均值为84.39%,且为三者中最大;术后比格犬BMD并未明显降低。体重、BMD、瘦素(leptin,LP)、VFA、高密度脂蛋白(high-density lipoprotein,HDL)与SFA相关。SFA、体重、低密度脂蛋白(low-density lipoprotein,LDL)、内脏脂肪素(visfatin,VFN)与BMD相关。结论去势比格犬模型可用于研究绝经后雌激素缺乏所引起的脂肪代谢变化,但短期内BMD并未明显丢失,骨、脂肪代谢之间存在交互作用。