LAUSR

Abstract Beige adipose tissue is induced in humans in response to cold, due in part to sympathetic nervous system (SNS) activation. We have previously found that mast cells promote seasonal induction of beige adipose tissue in humans and that in vitro mast cells sensed the cold and released histamine, promoting adipocyte beiging through activation of PKA (1). In recent studies, subcutaneous white adipose tissue (SC WAT) beiging was induced in lean and obese participants in response to repeated cold application (30 min ice pack for 10 days) in the summer (2). Interestingly, UCP1 and TMEM26, which are beige adipose markers, were induced in the cold-treated and non-treated, contralateral leg (2). We performed multiplex analysis of gene expression with the Nanostring nCounter system (with a probe set containing genes for specific immune cell markers, cytokines, and chemokines) on the SC WAT from this cohort of lean subjects to identify factors that promote or inhibit beiging. Multivariate analysis identified mast cell tryptase (r=0.77; P=0.003; n=12) and CCL26, a chemokine for mast cells, (r=0.71; P=0.009; n=12) as genes whose change correlated positively with the change in UCP1 in SC WAT of the cold treated leg, suggesting that mast cells are involved in SC WAT beiging. Immunohistochemistry was used to quantitate mast cell recruitment and degranulation into SC WAT. Mast cells increased in number in SC WAT of both the cold treated and contralateral legs in lean (1.6-fold increase (P<0.01)), but not obese subjects. However, there was an increase in the number of degranulated mast cells in SC WAT of the cold treated (P<0.0001) and contralateral (P<0.01) legs of both lean and obese subjects, suggesting that SNS-induced norepinephrine (NE) stimulated mast cell degranulation. To examine this in vitro, norepinephrine was added to cultured mast cells and histamine release was measured; NE potently stimulated histamine release (P<0.0001). In conclusion, cold stimulated mast cell recruitment and degranulation in SC WAT of lean and obese research participants, suggesting that mast cells promote adipose beiging through the release of histamine or other products. References: 1. Finlin BS, Zhu B, Confides AL, Westgate PM, Harfmann BD, Dupont-Versteegden EE, et al. Mast Cells Promote Seasonal White Adipose Beiging in Humans. Diabetes. 2017;66(5):1237-46. 2. Finlin BS, Memetimin H, Confides AL, Kasza I, Zhu B, Vekaria HJ, et al. Human adipose beiging in response to cold and mirabegron. JCI Insight. 2018;3(15).