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

战略研究重点：生物科学促进健康摘要许多流行病学、临床和实验研究表明，皮肤功能和全身代谢动态平衡之间存在联系。例如，炎症性皮肤病牛皮癣是2型糖尿病发生的独立危险因素，牛皮癣的存在是T2D进展和严重程度的强烈预测因素。此外，一些皮肤特异的转基因小鼠模型显示出全身葡萄糖稳态改变。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。我们提出了一种皮肤-坐式新陈代谢控制轴，在牛皮癣等情况下可能会变得功能失调，并对身体产生系统性影响。为了研究这一假设，我们将采用两种主要的实验方法。(1)在征得患者同意的情况下，从整形手术中获得的人体外植体皮肤将被培养并用咪喹莫特治疗，以诱导牛皮癣样表型。条件培养液(CM)将从这些组织中收集，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。然后这些组织将被用于组织分析，并将测量CM中的分泌物。另一种实验方法(2)将涉及研究咪喹莫特-小鼠牛皮癣模型的代谢表型。这将通过进行ipGTT和ipITT以及组织基因分析来完成。项目目标：了解皮肤如何对全身葡萄糖和脂肪稳态的调节做出贡献。描述：越来越多的证据表明皮肤功能和葡萄糖稳态之间存在联系。牛皮癣是患2型糖尿病的独立危险因素，而几种皮肤特异的转基因小鼠模型显示出葡萄糖代谢的改变(1，2)。这意味着皮肤内特定的信号通路调节葡萄糖的稳态。其潜在机制尚不清楚，但可能与皮肤内分泌功能有关。假设：我们提出了一个新的调节轴，通过它来自皮肤的分泌物功能来调节全身的葡萄糖和脂肪代谢。皮肤在解剖学上与皮下脂肪组织(SAT)相邻，后者被认为是全身新陈代谢的关键器官。体外和体内模型以及人类移植皮肤和Sat将被用于进行以下实验：-用咪喹莫特(Imquimod)治疗的人和小鼠皮肤的炎症性银屑病样表型的特征-皮肤对Sat和胰岛的治疗，以评估皮肤分泌物对关键代谢组织的功能-对银屑病ImQ小鼠模型的代谢表型的特征这些研究将促进对皮肤如何调节代谢动态平衡以及适应整个生命过程中健康老龄化的BBSRC优先领域的理解。

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.