Systematic metabolomic studies identified adult adiposity biomarkers with acetylglycine associated with fat loss in vivo

Obesity is associated with various adverse health outcomes. Body fat (BF) distribution is recognized as an important factor of negative health consequences of obesity. Although metabolomics studies, mainly focused on body mass index (BMI) and waist circumference, have explored the biological mechanisms involved in the development of obesity, these proxy composite measures are not accurate and cannot reflect BF distribution, and thus may hinder accurate assessment of metabolic alterations and differential risk of metabolic disorders among individuals presenting adiposity differently throughout the body. Thus, the exact relations between metabolites and BF remain to be elucidated. Here, we aim to examine the associations of metabolites and metabolic pathways with BF traits which reflect BF distribution. We performed systematic untargeted serum metabolite profiling and dual-energy X-ray absorptiometry (DXA) whole body fat scan for 517 Chinese women. We jointly analyzed DXA-derived four BF phenotypes to detect cross-phenotype metabolite associations and to prioritize important metabolomic factors. Topology-based pathway analysis was used to identify important BF-related biological processes. Finally, we explored the relationships of the identified BF-related candidate metabolites with BF traits in different sex and ethnicity through two independent cohorts. Acetylglycine, the top distinguished finding, was validated for its obesity resistance effect through in vivo studies of various diet-induced obese (DIO) mice. Eighteen metabolites and fourteen pathways were discovered to be associated with BF phenotypes. Six of the metabolites were validated in varying sex and ethnicity. The obesity-resistant effects of acetylglycine were observed to be highly robust and generalizable in both human and DIO mice. These findings demonstrate the importance of metabolites associated with BF distribution patterns and several biological pathways that may contribute to obesity and obesity-related disease etiology, prevention, and intervention. Acetylglycine is highlighted as a potential therapeutic candidate for preventing excessive adiposity in future studies.

肥胖与多种不良健康结果相关联。身体脂肪（BF）分布被视为肥胖负面健康后果的重要因素。尽管代谢组学研究发现，主要关注体重指数（BMI）和腰围的研究已探索了肥胖发展涉及的生物学机制，但这些代理复合指标并不准确，无法反映身体脂肪分布，因此可能阻碍对个体全身不同部位脂肪分布所呈现的代谢改变和代谢性疾病风险差异的准确评估。因此，代谢物与身体脂肪之间的确切关系尚待阐明。在此，我们旨在检验代谢物和代谢通路与反映身体脂肪分布的身体脂肪特征的关联。我们对517名中国女性进行了系统的非靶向血清代谢物分析，并使用双能X射线吸收法（DXA）进行全身脂肪扫描。我们联合分析了由DXA得出的四种身体脂肪表型，以检测跨表型代谢物关联并优先考虑重要的代谢组学因素。基于拓扑学的通路分析被用于识别重要的与身体脂肪相关的生物学过程。最终，我们通过两个独立的队列探讨了所识别的与身体脂肪相关的候选代谢物与不同性别和种族的身体脂肪特征之间的关系。乙酰甘氨酸，作为最显著的发现，通过多种饮食诱导肥胖（DIO）小鼠的体内研究验证了其抗肥胖作用。共发现了与身体脂肪表型相关的18种代谢物和14条通路。其中6种代谢物在不同性别和种族中得到了验证。乙酰甘氨酸的抗肥胖作用在人类和DIO小鼠中均表现出高度稳健和普遍性。这些发现证明了与身体脂肪分布模式相关的代谢物以及可能有助于肥胖及其相关疾病病因、预防和干预的数条生物学通路的重要性。乙酰甘氨酸被突出显示为未来研究中预防过度肥胖的潜在治疗候选物。