Human Antigen R (HuR) Regulates Structure and Function of Brown Adipose Tissue

Abstract

Human antigen R (HuR) is an RNA binding protein widely expressed throughout the body, including in both white (WAT) and brown (BAT) adipose tissue. Recent work from our lab has shown that adipocyte‐specific HuR knockout (adipo‐HuR−/−) mice gain less weight following a high fat diet (HFD) than the wild type (WT) controls. In this study, we focused on the role of HuR deletion on the function of BAT, which mediates non‐shivering thermogenesis.Our results show that, when subjected to a cold stress (4°C), HFD‐fed adipo‐HuR−/− mice are less cold tolerant compared to their WT counterparts. However, when the cold challenge was repeated with chow fed mice, there was no difference between the HuR knockout and wildtype mice in their ability to thermoregulate, suggesting that a change induced by high fat feeding rendered the adipo‐HuR−/− mice less cold tolerant. Histological analysis revealed that, while the BAT of the chow fed adipo‐HuR−/− mice appeared normal, following HFD, the BAT from adipo‐HuR−/− mice appears less dense with a cell size that more closely resembles WAT. Since uncoupling protein‐1 (UCP1) plays a key role in BAT mitochondrial uncoupling and non‐shivering thermogenic regulation, we assessed the ability of HuR to directly mediate UCP1 mRNA expression. Interestingly, analysis of the UCP1 mRNA sequence predicts at least four distinct HuR binding sites in the UCP1 3′UTR, and our data shows that UCP1 mRNA expression is decreased in BAT from adipo‐HuR−/− mice.In conclusion, our results indicate that HuR regulates both the structure and function of BAT, at least in part through direct modulation of UCP1 mRNA expression.Support or Funding InformationThis work was supported by a University of Cincinnati Heart, Lung, and Vascular Institute Near Horizons Grant (MT, APO).