Objectives

The skin is the largest sensory organ of the human body and plays a fundamental role in regulating body temperature. However, adaptive alterations in skin functions and morphology have only vaguely been associated with physiological responses to cold stress or sensation of ambient temperatures. We previously found that loss of acyl-CoA-binding protein (ACBP) in keratinocytes upregulates lipolysis in white adipose tissue and alters hepatic lipid metabolism, suggesting a link between epidermal barrier functions and systemic energy metabolism.

Methods

To assess the physiological responses to loss of ACBP in keratinocytes in detail, we used full-body ACBP^−/− and skin-specific ACBP^−/− knockout mice to clarify how loss of ACBP affects 1) energy expenditure by indirect calorimetry, 2) response to high-fat feeding and a high oral glucose load, and 3) expression of brown-selective gene programs by quantitative PCR in inguinal WAT (iWAT). To further elucidate the role of the epidermal barrier in systemic energy metabolism, we included mice with defects in skin structural proteins (ma/ma Flg^ft/ft) in these studies.

Results

We show that the ACBP^−/− mice and skin-specific ACBP^−/− knockout mice exhibited increased energy expenditure, increased food intake, browning of the iWAT, and resistance to diet-induced obesity. The metabolic phenotype, including browning of the iWAT, was reversed by housing the mice at thermoneutrality (30 °C) or pharmacological β-adrenergic blocking. Interestingly, these findings were phenocopied in flaky tail mice (ma/ma Flg^ft/ft). Taken together, we demonstrate that a compromised epidermal barrier induces a β-adrenergic response that increases energy expenditure and browning of the white adipose tissue to maintain a normal body temperature.

Conclusions

Our findings show that the epidermal barrier plays a key role in maintaining systemic metabolic homeostasis. Thus, regulation of epidermal barrier functions warrants further attention to understand the regulation of systemic metabolism in further detail.

中文翻译：

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表皮酰基辅酶A结合蛋白对于全身能量稳态是必不可少的

目标

皮肤是人体最大的感觉器官，在调节体温方面起着基础性作用。然而，皮肤功能和形态的适应性改变仅与对冷应激或环境温度感觉的生理反应有模糊的联系。我们之前发现角质形成细胞中酰基辅酶A结合蛋白（ACBP）的缺失会上调白色脂肪组织中的脂肪分解并改变肝脏脂质代谢，表明表皮屏障功能与全身能量代谢之间存在联系。

方法

为了详细评估角质形成细胞中 ACBP 损失的生理反应，我们使用全身 ACBP ^-/-和皮肤特异性 ACBP ^-/-基因敲除小鼠来阐明 ACBP 的损失如何影响 1) 间接量热法的能量消耗，2)对高脂肪喂养和高口服葡萄糖负荷的反应，以及 3) 通过定量 PCR 在腹股沟 WAT (iWAT) 中表达棕色选择性基因程序。为了进一步阐明表皮屏障在全身能量代谢中的作用，我们在这些研究中纳入了皮肤结构蛋白 ( ma/ma Flg ^ft/ft )缺陷的小鼠。

结果

我们表明 ACBP ^-/-小鼠和皮肤特异性 ACBP ^-/-基因敲除小鼠表现出能量消耗增加、食物摄入增加、iWAT 褐变以及对饮食引起的肥胖的抵抗力。代谢表型，包括 iWAT 的褐变，通过将小鼠置于热中性 (30 °C) 或药理学 β-肾上腺素能阻断来逆转。有趣的是，这些发现在片状尾小鼠（ma/ma Flg ^ft/ft）中进行了表型复制。总之，我们证明受损的表皮屏障会诱导 β-肾上腺素能反应，从而增加能量消耗和白色脂肪组织的褐变以维持正常体温。

结论

我们的研究结果表明，表皮屏障在维持全身代谢稳态方面起着关键作用。因此，表皮屏障功能的调节需要进一步关注以更详细地了解全身代谢的调节。