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Abstract：
BACKGROUND: Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD.
METHODS: Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed.
RESULTS: In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders.
CONCLUSIONS: Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946.
METHODS: Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed.
RESULTS: In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders.
CONCLUSIONS: Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946.
摘要：
背景：生长分化因子15（GDF15）是一种mitokine，其中的作用,总或H特异性，在调节肥胖相关疾病的能量代谢和体内平衡，如代谢功能障碍相关的脂肪变性肝病（MASLD），在成年人中还没有完全阐明。我们旨在调查GDF15的禁食和刺激水平，总和H特异性，葡萄糖依赖性促胰岛素多肽（GIP）和C肽，在两项生理学介入研究中：一项关注肥胖，和另一个在MASLD上。
方法：研究1调查了体重正常或肥胖的个体，接受3小时混合膳食测试(MMT);和研究2,检查了患有MASLD的成年人和接受120分钟口服葡萄糖耐量测试(OGTT)的对照。总和H特异性GDF15与临床的探索性相关性，还进行了激素和代谢组学/脂质组学参数。
结果：在研究1中，每个体重组包括15个个体。两组之间的空腹和餐后总和H特异性GDF15相似，而GIP在较瘦的个体中明显较高，并且在MMT后上调。与瘦受试者相比，肥胖人群的基线和餐后C肽明显升高。较瘦的个体GIP较高，在MMT后上调，而C肽及其MMT后的总体AUC在肥胖患者中与瘦受试者相比显著升高。在研究2中,评估了27个个体。空腹总GDF15相似，但MASLD患者餐后总GDF15水平明显高于对照组。GIP和C-肽保持不受影响。GDF15的餐后过程聚集在甘油三酯和丙氨酸循环分子中，在MASLD下被强烈提升，并构成了健康状态和MASLD状态之间最显着的区分分子。我们还提出了总和H特异性GDF15与大量脂质亚种的曲线下面积增量的稳健正相关，在对混杂因素进行调整后，这仍然很重要。
结论：血清GDF15水平与高血脂个体的体重状态没有差异，其他代谢健康个体也没有差异。相比之下,在基线时，MASLD患者的GDF15水平显着增加，并且与OGTT期间的健康参与者相比，它们仍然显着升高。指出GDF15作为mitokine的作用，在MASLD的病理生理学和可能的治疗中具有重要作用。试验注册ClinicalTrials.govNCT03986684，NCT04430946。
方法：研究1调查了体重正常或肥胖的个体，接受3小时混合膳食测试(MMT);和研究2,检查了患有MASLD的成年人和接受120分钟口服葡萄糖耐量测试(OGTT)的对照。总和H特异性GDF15与临床的探索性相关性，还进行了激素和代谢组学/脂质组学参数。
结果：在研究1中，每个体重组包括15个个体。两组之间的空腹和餐后总和H特异性GDF15相似，而GIP在较瘦的个体中明显较高，并且在MMT后上调。与瘦受试者相比，肥胖人群的基线和餐后C肽明显升高。较瘦的个体GIP较高，在MMT后上调，而C肽及其MMT后的总体AUC在肥胖患者中与瘦受试者相比显著升高。在研究2中,评估了27个个体。空腹总GDF15相似，但MASLD患者餐后总GDF15水平明显高于对照组。GIP和C-肽保持不受影响。GDF15的餐后过程聚集在甘油三酯和丙氨酸循环分子中，在MASLD下被强烈提升，并构成了健康状态和MASLD状态之间最显着的区分分子。我们还提出了总和H特异性GDF15与大量脂质亚种的曲线下面积增量的稳健正相关，在对混杂因素进行调整后，这仍然很重要。
结论：血清GDF15水平与高血脂个体的体重状态没有差异，其他代谢健康个体也没有差异。相比之下,在基线时，MASLD患者的GDF15水平显着增加，并且与OGTT期间的健康参与者相比，它们仍然显着升高。指出GDF15作为mitokine的作用，在MASLD的病理生理学和可能的治疗中具有重要作用。试验注册ClinicalTrials.govNCT03986684，NCT04430946。
