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

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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.