Taking steps towards harnessing signals from skin to promote metabolic health

McArdle professor Caroline Alexander has been intrigued by observations that connect the properties of skin with a switch of metabolism that promotes metabolic health.  This healthy metabolic status has been described for decades—principally in response to calorie restriction.  For example, humans are among a huge range of organisms that respond to reduced calorie intake with positive health outcomes, such as a dramatic resistance to tumor development, better insulin sensitivity and longer life.  Although some candidate physiological effectors have been described, there is still no clear picture of how calorie restriction works. An important regulator of mammalian energetics is body temperature homeostasis, and indeed there are many ways that mammals make sufficient heat to maintain a constant body temperature.  Each reaction is associated with different circulating molecules and a recalculation of energy consumption and reserves, leading to the suggestion that these reactions could provide an explanation for a switch of metabolic status. In this paper just published in Nature Communications, Riley et al. show that the thermal properties of skin are highly reactive.  Depending upon the exact diet fed to mice, their skin becomes more- or less-heat permeable: When skin becomes more heat permeable, the demand for heat production is increased.  When mice are fed a high fat diet, the majority of lipids are delivered to skin— indeed skin turns out to be the largest site for assimilation of dietary fat, where lipids comprise the building blocks of the thermal barrier.  Within days the properties of skin are changed to become less heat permeable and, in contrast to other organs, a single fat bolus persists for weeks in skin. Vice versa, when mice are fed a health-promoting diet—in this case, a diet with low levels of an amino acid, isoleucine—their skin becomes more heat permeable, a preamble to the establishment of a healthy lean weight, regardless of the consumption of a Western diet.  Riley et al. found that calorie restriction dramatically depletes skin, which becomes resistant to acquiring the dietary lipids. Although adipose and liver have long been considered to be the organs that coordinate the response to calorie restriction, this study could place skin front and center of the responder tissues. To search out the molecular basis of altered skin properties, this paper includes state-of-the-art mass spectroscopy of the skin lipidome. The authors’ focus on skin-associated lipids started with observations of genetically altered mice, where the loss of specific lipid species from skin led to systemic metabolic changes, such as resistance to diet-induced obesity.  Riley et al. show that altered skin properties align with changes in lipids made by both keratinocytes and sebocytes—these cell types are responsible for the production of the epidermal stratum corneum and the sebum respectively. It will be important to find out whether these cell types collaborate to maintain a balance of skin function. As well as members of the Alexander lab at the McArdle Laboratory, the skills of collaborators from across the University of Wisconsin campus and beyond are reflected in this paper, including experts in the impact of diet upon metabolic health (Hermsmeyer, MacDougald, Yen, Trautman and Lamming), and in the mass spectrometric analysis of lipids (Barrett-Wilt, Jain and Simcox). In sum, this paper is the latest contribution to a highly innovative line of research. The skin is a huge, under-explored organ with great potential to switch the metabolic program operating in mammals to one that promotes metabolic health.  Next on the agenda for the Alexander lab is to test tumor susceptibility for mice with engineered skins.