Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada.
Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada; Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2G3, Canada.
Cell Rep. 2024 Aug 27;43(8):114573. doi: 10.1016/j.celrep.2024.114573. Epub 2024 Jul 31.
Growth differentiation factor 15 (GDF15) is a peptide with utility in obesity, as it decreases appetite and promotes weight loss. Because obesity increases the risk for type 2 diabetes (T2D) and cardiovascular disease, it is imperative to understand the cardiovascular actions of GDF15, especially since elevated GDF15 levels are an established biomarker for heart failure. As weight loss should be encouraged in the early stages of obesity-related prediabetes/T2D, where diabetic cardiomyopathy is often present, we assessed whether treatment with GDF15 influences its pathology. We observed that GDF15 treatment alleviates diastolic dysfunction in mice with T2D independent of weight loss. This cardioprotection was associated with a reduction in cardiac inflammation, which was likely mediated via indirect actions, as direct treatment of adult mouse cardiomyocytes and differentiated THP-1 human macrophages with GDF15 failed to alleviate lipopolysaccharide-induced inflammation. Therapeutic manipulation of GDF15 action may thus have utility for both obesity and diabetic cardiomyopathy.
生长分化因子 15（GDF15）是一种在肥胖症中有应用价值的肽，因为它可以降低食欲并促进体重减轻。由于肥胖会增加 2 型糖尿病（T2D）和心血管疾病的风险，因此了解 GDF15 的心血管作用至关重要，特别是因为升高的 GDF15 水平是心力衰竭的既定生物标志物。由于在肥胖相关的糖尿病前期/T2D 的早期阶段应该鼓励减轻体重，而此时通常存在糖尿病心肌病，因此我们评估了 GDF15 治疗是否会影响其病理学。我们观察到，GDF15 治疗可减轻 T2D 小鼠的舒张功能障碍，而与体重减轻无关。这种心脏保护作用与心脏炎症的减少有关，这可能是通过间接作用介导的，因为直接用 GDF15 治疗成年小鼠心肌细胞和分化的 THP-1 人巨噬细胞未能减轻脂多糖诱导的炎症。因此，对 GDF15 作用的治疗性操作可能对肥胖症和糖尿病性心肌病都有作用。
