Springer Margherita, Meugnier Emmanuelle, Schnabl Katharina, Hof Kevin Sebastiaan, Champy Marie-France, Sorg Tania, Petit-Demoulière Benoit, Germain Natacha, Galusca Bogdan, Estour Bruno, Vidal Hubert, Klingenspor Martin, Hager Jörg
Société des Produits Nestlé S.A., Nestlé Institute of Health Sciences, Lausanne, Switzerland.
Chair for Molecular Nutritional Medicine, Technical University of Munich (TUM) School of Life Sciences, Technical University of Munich, Freising, Germany.
Front Endocrinol (Lausanne). 2024 Dec 4;15:1448107. doi: 10.3389/fendo.2024.1448107. eCollection 2024.
Overweight and obesity affects millions of individuals worldwide and consequently represents a major public health concern. Individuals living with overweight and obesity have difficulty maintaining a low body weight due to known physiological mechanisms which prevent further weight loss and drive weight regain. In contrast, mechanisms which promote low body weight maintenance receive less attention and are largely unknown. To uncover these intrinsic mechanisms, we investigated a human cohort of constitutionally thin (CT) individuals which maintain a low body weight and are resistant to weight gain despite exposure to an obesogenic environment.
To identify novel genes that contribute to low body weight maintenance, we performed transcriptomics on adipose tissue biopsies collected from CT and normal body weight (NBW) individuals and identified sulfotransferase 1A1 (SULT1A1) as a target for further investigation in mice. Sult1a1 knockout (KO) mice were fed a standard diet to assess the impact of Sult1a1 deletion on metabolic traits. To determine if high-fat feeding recapitulated the CT weight gain resistance phenotype, Sult1a1 KO mice were fed a high-fat diet for 13-weeks. A subset of wild-type and Sult1a1 KO mice from the standard diet were further analyzed for characterization of adipose tissue respiratory capacity.
In comparison to NBW controls, adipose tissue from CT individuals expresses less SULT1A1. Sult1a1 KO mice weigh 10% less at the end of the study period and on a high-fat diet, Sult1a1 KO mice tended to gain less weight and had reduced fat mass at 14-weeks of age. These changes were associated with reduced fasting insulin and lessened adipose tissue inflammation and fibrosis. Subcutaneous adipose tissue from Sult1a1 KO mice on a standard chow diet had elevated leak respiration, uncoupling protein 1 (UCP1) expression and increased expression of a mitochondrial marker, VDAC, associating Sult1a1 deletion to adipose tissue browning.
Our results associate Sult1a1 deletion with a tendency for lower body weight through remodeling of white adipose tissue towards a brown phenotype. The presence of UCP1, the expression of an additional mitochondrial protein and increased respiratory capacity suggest browning of the subcutaneous adipose tissue depot of Sult1a1 KO mice.
超重和肥胖影响着全球数百万人，因此是一个重大的公共卫生问题。由于已知的生理机制会阻止体重进一步减轻并导致体重反弹，超重和肥胖个体难以维持低体重。相比之下，促进低体重维持的机制较少受到关注，而且在很大程度上尚不明确。为了揭示这些内在机制，我们对一组体质消瘦（CT）个体进行了研究，这些个体尽管处于致胖环境中，但仍能维持低体重且不易增重。
为了确定有助于维持低体重的新基因，我们对从CT个体和正常体重（NBW）个体采集的脂肪组织活检样本进行了转录组学分析，并确定磺基转移酶1A1（SULT1A1）为在小鼠中进一步研究的靶点。给Sult1a1基因敲除（KO）小鼠喂食标准饮食，以评估Sult1a1缺失对代谢特征的影响。为了确定高脂喂养是否重现了CT体重增加抗性表型，给Sult1a1 KO小鼠喂食高脂饮食13周。对来自标准饮食组的一部分野生型和Sult1a1 KO小鼠进一步分析，以表征脂肪组织的呼吸能力。
与NBW对照组相比，CT个体的脂肪组织中SULT1A1表达较少。在研究期结束时，Sult1a1 KO小鼠体重轻10%，在高脂饮食条件下，14周龄时Sult1a1 KO小鼠体重增加倾向较小且脂肪量减少。这些变化与空腹胰岛素降低、脂肪组织炎症和纤维化减轻有关。在标准饲料喂养的Sult1a1 KO小鼠中，皮下脂肪组织的泄漏呼吸增加、解偶联蛋白1（UCP1）表达升高以及线粒体标记物电压依赖性阴离子通道（VDAC）表达增加，这表明Sult1a1缺失与脂肪组织褐变有关。
我们的结果表明，Sult1a1缺失通过将白色脂肪组织重塑为褐色表型而与较低体重倾向相关。UCP1的存在、另一种线粒体蛋白的表达以及呼吸能力的增加表明Sult1a1 KO小鼠皮下脂肪组织库发生了褐变。
