Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.01.277723v1?rss=1 Authors: Neess, D., Kruse, V., Marcher, A.-B., Waede, M. R., Vistisen, J., Moeller, P. M., Petersen, R., Brewer, J. R., Ma, T., Colleluori, G., Severi, I., Cinti, S., Gerhart-Hines, Z., Mandrup, S., Faergeman, N. J. Abstract: Objectives: Homeostatic regulation of body temperature is fundamental to mammalian physiology and is controlled by acute and chronic responses of local, endocrine and neuronal regulators. Although the skin is the largest sensory organ of the human body, and plays a fundamental role in regulating body temperature, it is surprising that adaptive alterations in skin functions and morphology only vaguely have been associated with physiological responses to cold stress or sensation of ambient temperatures. Methods: To unravel the physiological responses to a compromised epidermal barrier in detail we have used animal models with either defects in skin lipid metabolism (ACBP-/- and skin-specific ACBP-/- knockout mice) or defects in skin structural proteins (ma/ma Flg ft/ft). The primary objective was to clarify how defects in epidermal barrier function affect 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). Results: We show that mice with a compromised epidermal barrier function exhibit increased energy expenditure, increased food intake, browning of the iWAT, and resistance to diet-induced obesity. The metabolic phenotype, including browning of the iWAT, is reversed by housing the mice at thermoneutrality (30C) or by pharmacological beta-adrenergic blocking. These findings show that a compromised epidermal barrier induces a beta-adrenergic response that increases energy expenditure and browning of the white adipose tissue to maintain a normal body temperature. Conclusion: Our findings show that the epidermal barrier plays a key role in maintaining systemic metabolic homeostasis. Copy rights belong to original authors. Visit the link for more info