A PPARγ/long noncoding RNA axis regulates adipose thermoneutral remodeling in mice.
A PPARγ/long noncoding RNA axis regulates adipose thermoneutral remodeling in mice.
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DOI：
10.1172/jci170072
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发表时间：
2023-11-01
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储能白色脂肪细胞和产热米色脂肪细胞之间的相互作用导致肥胖和胰岛素抵抗。无论特殊生态位如何，脂肪细胞都需要核受体 PPARγ 的活性才能发挥正常功能。暴露于寒冷或肾上腺素信号传导可通过与 PPARγ 协同作用的多种途径丰富产热细胞；然而，PPARγ 允许白色脂肪组织优先采取生热或白色脂肪命运以响应饮食线索或热中性条件的分子机制尚未完全阐明。在这里，我们发现 PPARγ/长非编码 RNA (lncRNA) 轴整合了经典和非经典生热作用，以抑制热中性和饮食诱导的肥胖期间白色脂肪组织的散热。 lncRNA Lexis 的药理抑制或基因删除可增强解偶联蛋白 1 依赖性（UCP1 依赖性）和非依赖性产热作用。 Lexis 的脂肪特异性缺失可以抵消饮食引起的肥胖，提高胰岛素敏感性，并增加能量消耗。单核转录组学揭示 Lexis 调节独特的产热脂肪细胞群。我们系统地绘制了 Lexis 基序偏好，并表明它通过代谢 GWAS 基因和 WNT 调节剂 TCF7L2 的活性来调节生热程序。总的来说，我们的研究揭示了 PPARγ 和 WNT 之间的一种新的串扰模式，可以保持白色脂肪组织的可塑性。
Interplay between energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of specialized niche, adipocytes require the activity of the nuclear receptor PPARγ for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ; however, the molecular mechanisms by which PPARγ licenses white adipose tissue to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ/long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity. Pharmacologic inhibition or genetic deletion of the lncRNA Lexis enhances uncoupling protein 1–dependent (UCP1-dependent) and -independent thermogenesis. Adipose-specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT that preserves white adipose tissue plasticity.