Can The Skin Make You Fat?: Investigating the role of the skin in the regulation glucose and lipid homeostasis

皮肤会让你发胖吗？：研究皮肤在调节葡萄糖和脂质稳态中的作用

• 批准号: 1627277
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1627277
• 关键词: Skin; Make; Fat; Investigating; role

Strategic Research Priority: Bioscience for HealthAbstract Many epidemiological, clinical and experimental studies suggest a link between skin function and whole-body metabolic homeostasis. For example, the inflammatory skin disease psoriasis is an independent risk-factor for Type 2 diabetes development and presence of psoriasis is a strong predictor of T2D progression and severity. Moreover, some skin-specific transgenic mouse models display altered whole-body glucose homeostasis. This suggests an important role for skin in regulating whole-body glucose metabolism. However, the underlying mechanisms are unclear, but potentially relate to skin endocrine function. We propose a skin-sAT regulatory axis of metabolic control that could become dysfunctional in conditions such as psoriasis and have an impact systemically in the body. To investigate this hypothesis we will adopt two main experimental approaches. (1) Human explant skin obtained from plastic surgery operations, with patient consent, will be cultured and treated with the drug imiquimod to induce a psoriasis-like phenotype. Conditioned media (CM) will then be collected from these tissues and subsequently be used to treat other metabolically important tissues, such as subcutaneous adipose tissue and pancreatic islets. These tissues will then be used for tissue analysis and secretions in the CM will be measured. The other experimental approach (2) will involve investigating the metabolic phenotype of the imiquimod-mouse model of psoriasis. This will be done by carrying out ipGTT and ipITT and tissue gene analysis.Project Aim: To understand how skin contributes to the regulation of whole-body glucose and lipid homeostasis.Description:Accumulating evidence suggests a link between skin function and glucose homeostasis. Psoriasis is an independent risk factor for development of type 2 diabetes, whilst several skin-specific transgenic mouse models display altered glucose metabolism(1,2). This implies that specific signalling pathways within the skin regulate glucose homeostasis. The underlying mechanisms are unclear but are potentially related to skin endocrine function. Hypothesis: We propose a novel regulatory axis whereby secretions from the skin function to regulate whole-body glucose and lipid metabolism. Skin is located anatomically adjacent to subcutaneous adipose tissue (sAT), which is recognised as a crucial organ in whole-body metabolism(4). Therefore, a putative keratinocyte-sAT regulatory axis will be the main focus.In vitro and in vivo models and human explant skin and sAT will be used to conduct the following experiments: - Characterisation of the inflammatory psoriatic-like phenotype of human and mouse skin treated with imiquimod (IMQ)- Skin CM treatments of sAT and pancreatic islets to assess the function of secretions from the skin on key metabolic tissues- Characterisation of the metabolic phenotype of the IMQ mouse model of psoriasisThese studies will advance understanding of how skin regulates metabolic homeostasis and fit within the BBSRC priority area of healthy ageing across the life course.

许多流行病学、临床和实验研究表明，皮肤功能与全身代谢稳态之间存在联系。例如，炎症性皮肤病牛皮癣是2型糖尿病发展的独立危险因素，牛皮癣的存在是2型糖尿病进展和严重程度的一个强有力的预测因素。此外，一些皮肤特异性转基因小鼠模型显示出全身葡萄糖稳态的改变。这表明皮肤在调节全身葡萄糖代谢中起着重要作用。然而，潜在的机制尚不清楚，但可能与皮肤内分泌功能有关。我们提出了代谢控制的皮肤- sat调节轴，它可能在牛皮癣等疾病中变得功能失调，并对全身产生影响。为了研究这一假设，我们将采用两种主要的实验方法。(1)整形手术获得的人体外植皮肤，经患者同意后，将被培养并用药物咪喹莫特治疗，以诱导牛皮癣样表型。然后从这些组织中收集条件培养基（CM），随后用于治疗其他代谢重要的组织，如皮下脂肪组织和胰岛。这些组织将被用于组织分析，CM中的分泌物将被测量。另一种实验方法(2)将涉及研究牛皮癣伊米喹莫特小鼠模型的代谢表型。这将通过ipGTT和ipITT以及组织基因分析来完成。项目目标：了解皮肤如何促进全身葡萄糖和脂质稳态的调节。描述：越来越多的证据表明皮肤功能与葡萄糖稳态之间存在联系。牛皮癣是2型糖尿病发展的独立危险因素，而一些皮肤特异性转基因小鼠模型显示葡萄糖代谢改变（1,2）。这意味着皮肤内的特定信号通路调节葡萄糖稳态。潜在的机制尚不清楚，但可能与皮肤内分泌功能有关。假设：我们提出了一种新的调节轴，即皮肤分泌物调节全身葡萄糖和脂质代谢。皮肤在解剖学上与皮下脂肪组织（sAT）相邻，后者被认为是全身代谢的重要器官(4)。因此，一个假定的角化细胞- sat调节轴将是主要的焦点。采用体外和体内模型及人体外植皮肤和sAT进行以下实验：IMQ治疗的人类和小鼠皮肤炎症性银屑病样表型的表征- sAT和胰岛的皮肤CM治疗以评估皮肤分泌物对关键代谢组织的功能- IMQ牛皮癣小鼠模型的代谢表型表征这些研究将促进对皮肤如何调节代谢稳态的理解，并符合BBSRC在整个生命过程中健康衰老的优先领域。