Serum and Adipose Tissue Amino Acid Homeostasis in the Metabolically Healthy Obese

A subgroup of obese individuals, referred to as metabolically healthy obese (MHO), have preserved insulin sensitivity and a normal lipid profile despite being obese. The molecular basis for this improved cardiometabolic profile remains unclear. Our objective was to integrate metabolite and gene expression profiling to elucidate the molecular distinctions between MHO and metabolically unhealthy obese (MUO) phenotypes. A subset of individuals were selected from the Diabetes Risk Assessment study and classified into three groups using anthropometric and clinical measurements: lean healthy (LH), MHO, and MUO. Serum metabolites were profiled using gas chromatography coupled to mass spectrometry. Multivariate data analysis uncovered metabolites that differed between groups, and these were subsequently validated by capillary electrophoresis coupled to mass spectrometry. Subcutaneous adipose tissue (SAT) gene expression profiling using microarrays was performed in parallel. Amino acids were the most relevant class of metabolites distinguishing MHO from MUO individuals. Serum levels of glutamic acid, valine, and isoleucine were positively associated (i.e., LH MHO > MUO) with HbA1c values. Concomitantly, SAT gene expression profiling revealed that genes related to branched-chain amino acid catabolism and the tricarboxylic acid cycle were less down-regulated in MHO individuals compared to MUO individuals. Together, this integrated analysis revealed that MHO individuals have an intermediate amino acid homeostasis compared to LH and MUO individuals.

代谢健康型肥胖（metabolically healthy obese, MHO）是肥胖人群中的一个亚群，尽管体型肥胖，但这类人群仍保留胰岛素敏感性且血脂谱正常。这类人群所具备的更佳心脏代谢表型的分子基础目前仍未明确。本研究旨在整合代谢组与基因表达谱分析，阐明代谢健康型肥胖（MHO）与代谢异常型肥胖（metabolically unhealthy obese, MUO）表型之间的分子差异。研究从糖尿病风险评估（Diabetes Risk Assessment）研究队列中选取部分受试者，通过人体测量学与临床检测指标将其分为三组：健康瘦体型组（lean healthy, LH）、代谢健康型肥胖组（MHO）以及代谢异常型肥胖组（MUO）。采用气相色谱-质谱联用技术对血清代谢物进行检测分析；多变量数据分析筛选出组间存在差异的代谢物，随后通过毛细管电泳-质谱联用技术对这些差异代谢物进行验证。同时采用微阵列技术对皮下脂肪组织（subcutaneous adipose tissue, SAT）进行基因表达谱分析。氨基酸是区分MHO与MUO受试者最具代表性的代谢物类别。血清谷氨酸、缬氨酸及异亮氨酸水平与糖化血红蛋白（HbA1c）值呈正相关关系，即健康瘦体型组＞代谢健康型肥胖组＞代谢异常型肥胖组。与此同时，皮下脂肪组织基因表达谱分析显示，与MUO受试者相比，MHO受试者体内与支链氨基酸分解代谢及三羧酸循环相关的基因下调程度更低。综上，本整合分析结果表明，相较于健康瘦体型组与代谢异常型肥胖组受试者，代谢健康型肥胖组受试者的氨基酸稳态处于中间状态。