Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University, Beijing, China.
Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, China.
Theranostics. 2024 Aug 26;14(13):5316-5335. doi: 10.7150/thno.97046. eCollection 2024.
Enhancing white adipose tissue (WAT) browning combats obesity. The RIIβ subunit of cAMP-dependent protein kinase (PKA) is primarily expressed in the brain and adipose tissue. Deletion of the hypothalamic RIIβ gene centrally induces WAT browning, yet the peripheral mechanisms mediating this process remain unexplored. This study investigates the mechanisms underlying WAT browning in RIIβ-KO mice. Genetic approaches such as β3-adrenergic receptors (β3ARs) deletion and sympathetic denervation of WAT were utilized. Genome-wide transcriptomic sequencing and bioinformatic analysis were employed to identify potential mediators of WAT browning. siRNA assays were employed to knock down mTOR and lipin1 , while AAV-shRNAs were used for the same purpose . We found that WAT browning substantially contributes to the lean and obesity-resistant phenotypes of RIIβ-KO mice. The WAT browning can be dampened by βARs deletion or WAT sympathetic denervation. We identified that adipocytic mTOR and lipin1 may act as mediators of the WAT browning. Inhibition of mTOR or lipin1 abrogates WAT browning and hinders the lean phenotype of RIIβ-KO mice. In human subcutaneous white adipocytes and mouse white adipocytes, βAR stimulation can activate mTOR and causes lipin1 nuclear translocation; knockdown of mTOR and Lipin1 mitigates WAT browning-associated gene expression, impedes mitochondrial activity. Moreover, mTOR knockdown reduces lipin1 level and nuclear translocation, indicating that lipin1 may act downstream of mTOR. Additionally, knockdown of mTOR and Lipin1 diminished WAT browning and increased adiposity. The βAR-activated mTOR-lipin1 axis mediates WAT browning, offering new insights into the molecular basis of PKA-regulated WAT browning. These findings provide potential adipose target candidates for the development of drugs to treat obesity.
增强白色脂肪组织（WAT）褐变可对抗肥胖。环磷酸腺苷依赖性蛋白激酶（PKA）的 RIIβ 亚基主要在大脑和脂肪组织中表达。下丘脑 RIIβ 基因缺失会中枢性诱导 WAT 褐变，但介导此过程的外周机制仍未被探索。本研究旨在探究 RIIβ-KO 小鼠 WAT 褐变的机制。采用了基因敲除等方法，如β3-肾上腺素能受体（β3AR）缺失和 WAT 去交感神经支配。我们还进行了全基因组转录组测序和生物信息学分析，以鉴定 WAT 褐变的潜在介质。利用 siRNA 敲低 mTOR 和 Lipin1，同时使用 AAV-shRNAs 实现相同目的。我们发现 WAT 褐变显著促成了 RIIβ-KO 小鼠的瘦和肥胖抵抗表型。βAR 缺失或 WAT 去交感神经支配可抑制 WAT 褐变。我们发现脂肪细胞中的 mTOR 和 Lipin1 可能作为 WAT 褐变的介质。抑制 mTOR 或 Lipin1 可阻断 WAT 褐变并阻碍 RIIβ-KO 小鼠的瘦表型。在人皮下白色脂肪细胞和小鼠白色脂肪细胞中，βAR 刺激可激活 mTOR 并导致 Lipin1 核转位；敲低 mTOR 和 Lipin1 可减轻 WAT 褐变相关基因表达，阻碍线粒体活性。此外，mTOR 敲低会降低 Lipin1 水平和核转位，表明 Lipin1 可能作为 mTOR 的下游分子。此外，敲低 mTOR 和 Lipin1 会减少 WAT 褐变并增加脂肪堆积。βAR 激活的 mTOR-Lipin1 轴介导 WAT 褐变，为 PKA 调节的 WAT 褐变的分子基础提供了新的见解。这些发现为治疗肥胖症的药物开发提供了潜在的脂肪靶标候选物。
