Jaiswal Anil Kumar, Sadasivam Mohanraj, Aja Susan, Hamad Abdel Rahim A
Department of Pathobiology, Johns Hopkins University, Baltimore, MD 21205, United States.
Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, United States.
World J Diabetes. 2020 Apr 15;11(4):126-136. doi: 10.4239/wjd.v11.i4.126.
Obesity is a disease state with serious adverse metabolic complications, including glucose intolerance and type 2 diabetes that currently has no cure. Identifying and understanding roles of various modulators of body composition and glucose homeostasis is required for developing effective cures. Syndecan-1 (Sdc1) is a member of the heparan sulfate proteoglycan family that has mainly been investigated for its role in regulating proliferation and survival of epithelia and tumor cells, but little is known about its roles in regulating obesity and glucose homeostasis.
To examine the role of Sdc1 in regulating body fat and glucose metabolism.
We used female wild type and Sdc1 knockout (Sdc1 KO) mice on BALB/c background and multiple methods. Metabolic measurements (rates of oxygen consumption, carbon dioxide production, respiratory exchange ratio and energy expenditure) were performed using an open-flow indirect calorimeter with additional features to measure food intake and physical activity. Glucose intolerance and insulin resistance were measured by established tolerance test methods.
Although our primary goal was to investigate the effects of Sdc1 deficiency on body fat and glucose homeostasis, we uncovered that Sdc1 regulates multiple metabolic parameters. Sdc1KO mice have reduced body weight due to significant decreases in fat and lean masses under both chow and high fat diet conditions. The reduced body weight was not due to changes in food intakes, but Sdc1 KO mice exhibited altered feeding behavior as they ate more during the dark phase and less during the light phase than wild type mice. In addition, Sdc1 KO mice suffered from high rate of energy expenditure, glucose intolerance and insulin resistance.
These results reveal critical multisystem and opposing roles for Sdc1 in regulating normal energy balance and glucose homeostasis. The results will have important implications for targeting Sdc1 to modulate metabolic parameters. Finally, we offer a novel hypothesis that could reconcile the opposing roles associated with Sdc1 deficiency.
肥胖是一种伴有严重不良代谢并发症的疾病状态，包括目前无法治愈的葡萄糖不耐受和2型糖尿病。开发有效的治疗方法需要识别和理解各种身体成分和葡萄糖稳态调节因子的作用。Syndecan-1（Sdc1）是硫酸乙酰肝素蛋白聚糖家族的成员，主要研究其在调节上皮细胞和肿瘤细胞增殖与存活中的作用，但对其在调节肥胖和葡萄糖稳态中的作用知之甚少。
研究Sdc1在调节体脂和葡萄糖代谢中的作用。
我们使用了BALB/c背景的雌性野生型和Sdc1基因敲除（Sdc1 KO）小鼠，并采用了多种方法。使用具有测量食物摄入量和身体活动附加功能的开放式间接热量计进行代谢测量（氧气消耗率、二氧化碳产生率、呼吸交换率和能量消耗）。通过既定的耐受性测试方法测量葡萄糖不耐受和胰岛素抵抗。
尽管我们的主要目标是研究Sdc1缺乏对体脂和葡萄糖稳态的影响，但我们发现Sdc1调节多种代谢参数。在正常饮食和高脂饮食条件下，Sdc1 KO小鼠的体重均因脂肪和瘦体重显著降低而减轻。体重减轻并非由于食物摄入量的变化，但Sdc1 KO小鼠表现出摄食行为改变，因为它们在黑暗期比野生型小鼠吃得更多，而在光照期吃得更少。此外，Sdc1 KO小鼠存在高能量消耗率、葡萄糖不耐受和胰岛素抵抗。
这些结果揭示了Sdc1在调节正常能量平衡和葡萄糖稳态中关键的多系统和相反作用。这些结果对于将Sdc1作为调节代谢参数的靶点具有重要意义。最后，我们提出了一个新的假设，该假设可以解释与Sdc1缺乏相关的相反作用。
