Olfactory receptors (ORs) are present in tissues outside the olfactory system; however, the function of these receptors remains relatively unknown. Here, we determined that olfactory receptor 544 (Olfr544) is highly expressed in the liver and adipose tissue of mice and regulates cellular energy metabolism and obesity. Azelaic acid (AzA), an Olfr544 ligand, specifically induced PKA-dependent lipolysis in adipocytes and promoted fatty acid oxidation (FAO) and ketogenesis in liver, thus shifting the fuel preference to fats. After 6 weeks of administration, mice fed a high-fat diet (HFD) exhibited a marked reduction in adiposity. AzA treatment induced expression of PPAR-α and genes required for FAO in the liver and induced the expression of PPAR-γ coactivator 1-α (Ppargc1a) and uncoupling protein-1 (Ucp1) genes in brown adipose tissue (BAT). Moreover, treatment with AzA increased insulin sensitivity and ketone body levels. This led to a reduction in the respiratory quotient and an increase in the FAO rate, as indicated by indirect calorimetry. AzA treatment had similar antiobesogenic effects in HFD-fed ob/ob mice. Importantly, AzA-associated metabolic changes were completely abrogated in HFD-fed Olfr544^–/– mice. To our knowledge, this is the first report to show that Olfr544 orchestrates the metabolic interplay between the liver and adipose tissue, mobilizing stored fats from adipose tissue and shifting the fuel preference to fats in the liver and BAT.

中文翻译：

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嗅觉受体544通过使燃料偏向脂肪来减少肥胖

嗅觉受体（ORs）存在于嗅觉系统外的组织中。然而，这些受体的功能仍然相对未知。在这里，我们确定嗅觉受体544（Olfr544）在小鼠的肝脏和脂肪组织中高度表达，并调节细胞能量代谢和肥胖。壬二酸（AzA）是Olfr544的配体，可特异性地诱导脂肪细胞中PKA依赖性脂解，并促进肝脏中的脂肪酸氧化（FAO）和生酮作用，从而将燃料偏好转移到脂肪上。给药6周后，喂食高脂饮食（HFD）的小鼠脂肪明显减少。AzA处理诱导肝脏中PPAR-α的表达和FAO所需的基因，并诱导PPAR-γ辅助激活物1-α（Ppargc1a）和解偶联蛋白1（PPARgc1a）的表达。褐色脂肪组织（BAT）中的Ucp1）基因。此外，用AzA治疗可增加胰岛素敏感性和酮体水平。如间接量热法所示，这导致呼吸商减少和粮农组织比率增加。AzA治疗在HFD喂养的ob / ob小鼠中具有相似的抗肥胖作用。重要的是，HFD喂养的Olfr544 ^{– / –}小鼠完全消除了与AzA相关的代谢变化。据我们所知，这是第一个显示Olfr544协调肝脏和脂肪组织之间的代谢相互作用，从脂肪组织中调动储存的脂肪并将燃料偏好转移到肝脏和BAT中的脂肪的报告。