Farnesoid X Receptor alters adipose tissue architecture in mice and limits its storage capacity leading to metabolic derangements

The bile acid-activated nuclear receptor Farnesoid X receptor (FXR, NR1H4) has been implicated in the control of lipid and energy metabolism, but its role in fat tissue, where it is moderately expressed, is not understood. In view of the recent development of FXR-targeting therapeutics for treatment of human metabolic diseases, understanding the tissue-specific actions of FXR is essential. We show that transgenic mice expressing human FXR specifically in adipose tissue (aP2-hFXR) have markedly enlarged adipocytes and show extensive extracellular matrix remodelling. Ageing and exposure to obesogenic conditions revealed a strongly limited capacity for adipose expansion and development of fibrosis in adipose tissues of aP2-hFXR transgenic mice. This was associated with impaired lipid storage capacity, leading to elevated plasma free fatty acids, ectopic fat deposition in liver and muscle as well as whole-body insulin resistance. These studies establish that adipose FXR is a determinant of adipose tissue architecture and contributes to whole-body lipid homeostasis. Total RNA optained from 10 BAT and 8 WAT samples, where compaired in 2 by 2 different groups, consisting of biological replicates n=4,5

胆汁酸激活的核受体法尼醇X受体（Farnesoid X receptor, FXR, NR1H4）已被证实参与脂质与能量代谢的调控，但其在适度表达该受体的脂肪组织中的作用仍未明确。鉴于靶向FXR的治疗药物近年来在人类代谢疾病治疗领域取得进展，阐明FXR的组织特异性作用机制至关重要。本研究发现，在脂肪组织中特异性表达人源FXR的转基因小鼠（aP2-hFXR）其脂肪细胞显著肥大，并伴随广泛的细胞外基质重塑。随着年龄增长及致肥胖环境暴露，aP2-hFXR转基因小鼠的脂肪组织扩张能力严重受限，并出现脂肪纤维化。该表型与脂质储存能力受损相关，进而导致血浆游离脂肪酸水平升高、肝脏与肌肉异位脂肪沉积，以及全身胰岛素抵抗。本研究证实，脂肪组织FXR是脂肪组织结构的决定性调控因子，并参与全身脂质稳态的维持。本研究从10份棕色脂肪组织（brown adipose tissue, BAT）与8份白色脂肪组织（white adipose tissue, WAT）样本中提取总RNA，将样本分为两组进行两两对照分析，两组的生物学重复数分别为n=4与n=5。