Gaspar Rodrigo S, Delafiori Jeany, Zuccoli Giuliana, Carregari Victor Corasolla, Prado Thais P, Morari Joseane, Sidarta-Oliveira Davi, Solon Carina S, Catharino Rodrigo R, Araujo Eliana P, Martins-de-Souza Daniel, Velloso Licio A
Laboratory of Cell Signaling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil.
National Institute of Science and Technology on Neuroimmunomodulation, Rio de Janeiro, Brazil.
Am J Physiol Endocrinol Metab. 2023 Mar 1;324(3):E226-E240. doi: 10.1152/ajpendo.00231.2022. Epub 2023 Feb 1.
Obesity is one of the leading noncommunicable diseases in the world. Despite intense efforts to develop strategies to prevent and treat obesity, its prevalence continues to rise worldwide. A recent study has shown that the tricarboxylic acid intermediate succinate increases body energy expenditure by promoting brown adipose tissue thermogenesis through the activation of uncoupling protein-1; this has generated interest surrounding its potential usefulness as an approach to treat obesity. It is currently unknown how succinate impacts brown adipose tissue protein expression, and how exogenous succinate impacts body mass reduction promoted by a drug approved to treat human obesity, the glucagon-like-1 receptor agonist, liraglutide. In the first part of this study, we used bottom-up shotgun proteomics to determine the acute impact of exogenous succinate on the brown adipose tissue. We show that succinate rapidly affects the expression of 177 brown adipose tissue proteins, which are mostly associated with mitochondrial structure and function. In the second part of this study, we performed a short-term preclinical pharmacological intervention, treating diet-induced obese mice with a combination of exogenous succinate and liraglutide. We show that the combination was more efficient than liraglutide alone in promoting body mass reduction, food energy efficiency reduction, food intake reduction, and an increase in body temperature. Using serum metabolomics analysis, we showed that succinate, but not liraglutide, promoted a significant increase in the blood levels of several medium and long-chain fatty acids. In conclusion, exogenous succinate promotes rapid changes in brown adipose tissue mitochondrial proteins, and when used in association with liraglutide, increases body mass reduction. Exogenous succinate induces major changes in brown adipose tissue protein expression affecting particularly mitochondrial respiration and structural proteins. When given exogenously in drinking water, succinate mitigates body mass gain in a rodent model of diet-induced obesity; in addition, when given in association with the glucagon-like peptide-1 receptor agonist, liraglutide, succinate increases body mass reduction promoted by liraglutide alone.
肥胖是全球主要的非传染性疾病之一。尽管人们为制定预防和治疗肥胖的策略付出了巨大努力，但其在全球的患病率仍在持续上升。最近的一项研究表明，三羧酸中间体琥珀酸可通过激活解偶联蛋白-1促进棕色脂肪组织产热，从而增加身体能量消耗；这引发了人们对其作为治疗肥胖方法的潜在效用的兴趣。目前尚不清楚琥珀酸如何影响棕色脂肪组织蛋白表达，以及外源性琥珀酸如何影响经批准用于治疗人类肥胖的药物胰高血糖素样肽-1受体激动剂利拉鲁肽所促进的体重减轻。在本研究的第一部分，我们使用自下而上的鸟枪法蛋白质组学来确定外源性琥珀酸对棕色脂肪组织的急性影响。我们发现琥珀酸迅速影响177种棕色脂肪组织蛋白的表达，这些蛋白大多与线粒体结构和功能相关。在本研究的第二部分，我们进行了短期临床前药理学干预，用外源性琥珀酸和利拉鲁肽联合治疗饮食诱导的肥胖小鼠。我们发现，联合用药在促进体重减轻、降低食物能量效率、减少食物摄入量和提高体温方面比单独使用利拉鲁肽更有效。通过血清代谢组学分析，我们发现琥珀酸而非利拉鲁肽可显著提高几种中长链脂肪酸的血液水平。总之，外源性琥珀酸可促进棕色脂肪组织线粒体蛋白的快速变化，与利拉鲁肽联合使用时，可增加体重减轻。外源性琥珀酸可诱导棕色脂肪组织蛋白表达发生重大变化，尤其影响线粒体呼吸和结构蛋白。当通过饮用水外源性给予时，琥珀酸可减轻饮食诱导的肥胖啮齿动物模型中的体重增加；此外，当与胰高血糖素样肽-1受体激动剂利拉鲁肽联合使用时，琥珀酸可增加利拉鲁肽单独使用时所促进的体重减轻。
