Batrow Pierre-Louis, Caspar-Bauguil Sylvie, Rochet Nathalie, Gautier Nadine, Rousseau Anne-Sophie, Maret Marielle, Rekima Samah, Mouisel Etienne, Van Obberghen Emmanuel, Roux Christian H, Guillou Hervé, Postic Catherine, Wolfrum Christian, Langin Dominique, Amri Ez-Zoubir, Mothe-Satney Isabelle
Université Côte d'Azur, CNRS, Inserm, Adipocible Research Study Group, Institut de Biologie Valrose (iBV), Nice, France.
Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III University - Paul Sabatier (UPS), Toulouse, France; Department of Medical Biochemistry, Toulouse University Hospitals, France.
Mol Metab. 2025 Aug;98:102184. doi: 10.1016/j.molmet.2025.102184. Epub 2025 Jun 10.
Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear receptors involved in the control of lipid metabolism. The PPARα isoform is highly expressed in brown adipose tissue (BAT). However, its precise role in BAT remains unclear. Here, we aimed to investigate the role of PPARα in BAT of high fat diet-induced obese mice in a thermoneutral environment.
We used tamoxifen-inducible-BAT specific PPARα knockout mice (PPARαBATKO) that were housed at thermoneutrality to minimize BAT basal activation, fed a high-fat diet for 20 weeks and challenged with a β-adrenergic agonist (CL316,243) during the last week. Both male and female mice were studied.
Body weight and glucose tolerance tests were similar in both sexes and genotypes. However, BAT morphology was altered in PPARαBATKO mice, with more unilocular and larger lipid droplets compared to control mice, suggesting BAT impaired function. Indeed, when treated with CL316,243, both male and female mice had increased De Novo Lipogenesis (DNL), reflected by an increased expression of ChREBPβ and lipogenic enzymes ACLY, ACC1, FASN and SCD1. These changes were accompanied by an increase in fatty acids in triglycerides, and thus an increase in lipid storage. Moreover, lipid profiles in phospholipids were different, suggesting a modification in the membrane content with an increase of palmitoleate.
Altogether, our results reveal a key role for PPARα in DNL in BAT and in the regulation of lipid metabolism in HFD-induced obesity.
过氧化物酶体增殖物激活受体（PPARs）是参与脂质代谢调控的核受体。PPARα亚型在棕色脂肪组织（BAT）中高度表达。然而，其在BAT中的具体作用仍不清楚。在此，我们旨在研究PPARα在热中性环境下高脂饮食诱导的肥胖小鼠BAT中的作用。
我们使用他莫昔芬诱导的BAT特异性PPARα基因敲除小鼠（PPARαBATKO），将其饲养在热中性环境中以尽量减少BAT的基础激活，给予高脂饮食20周，并在最后一周用β-肾上腺素能激动剂（CL316,243）进行刺激。对雄性和雌性小鼠均进行了研究。
体重和葡萄糖耐量试验在性别和基因型上相似。然而，PPARαBATKO小鼠的BAT形态发生了改变，与对照小鼠相比，出现了更多的单泡且更大的脂滴，提示BAT功能受损。实际上，在用CL316,243处理后，雄性和雌性小鼠的从头脂肪生成（DNL）均增加，这通过ChREBPβ和脂肪生成酶ACLY、ACC1、FASN和SCD1表达的增加得以体现。这些变化伴随着甘油三酯中脂肪酸的增加，进而脂质储存增加。此外，磷脂中的脂质谱不同，表明膜成分发生了改变，棕榈油酸增加。
总之，我们的结果揭示了PPARα在BAT的DNL以及高脂饮食诱导的肥胖中脂质代谢调控中的关键作用。
