Increasing biological thermogenesis (the conversion of chemical energy to heat) has been proposed as an approach towards lowering blood glucose, improving insulin sensitivity and mitigating type 2 diabetes. Non-shivering thermogenesis occurs primarily in adipocytes that express uncoupling protein 1 (UCP1) including brown adipose tissue (BAT) and beige adipose tissue but does not substantially occur in white adipose tissue (WAT). To identify genes that regulate thermogenesis and BAT function, we recently compared genes expressed in paired human patient samples (n = 10) of the deep neck BAT located next to the carotid sheath and superficial subcutaneous WAT in the neck. We found UDP-glucuronide transferase 1A (UGT1A) is co-expressed in individuals with a high amount of the thermogenic protein uncoupling protein 1 (UCP1). This enzyme is known to glucuronidate metabolites, including bilirubin and xenobiotics, which increases their water solubility and excretion. Based on this function, we hypothesize UGT1A regulates BAT not through direct action of the enzyme but through modulating the availability of thermogenic molecules. Here, we characterized expression of different UGT1A isoforms in vivo and in vitro. Cold exposure is an effective method for activating BAT and increasing thermogenesis in mice. Interestingly, expression of multiple UGT1A isoforms, including UGT1A6a and UGT1A6b, are decreased in BAT of mice exposed to a cold environment (5°C) for 7 days. This finding is consistent with data in multiple publicly available datasets which have shown UGT1A6a/6b are decreased in cold exposure and other thermogenic stimuli. In vitro, most UGT1A isoforms were increased during the differentiation of murine brown adipocytes but only certain isoforms were differentially expressed during in vitro differentiation in human brown adipocytes. Based on these data, we propose that UGT1A may have a function related to thermogenesis and understanding its function could lead to novel approaches for activating BAT.
S. Kodani: None. M. Lynes: None. F. Shamsi: None. C. Wang: None. S. Sugimoto: None. R. Xue: None. T. Huang: None. A.P. White: None. A.M. Cypess: None. Y. Tseng: Consultant; Self; Boehringer Ingelheim International GmbH.
National Institutes of Health (R01DK07709, R01DK102898, T32DK007260)