Aberra Yonathan Tamrat, Yang Qianyi, Cowan Ashlyn, Gediksiz Bilge Yaylak, Thomas Mitchell, Gragirenes-Delgado David, Keita Foday, Civelek Mete
Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.
Department of Biology, University of Puerto Rico-Cayey, Cayey, Puerto Rico, USA.
Physiol Rep. 2025 Aug;13(15):e70513. doi: 10.14814/phy2.70513.
Metabolic syndrome, a constellation of cardiometabolic risk factors including abdominal obesity, predisposes individuals to type 2 diabetes and cardiovascular disease. One frequently replicated MetSyn genetic association signal is located near KLF14 and is linked to central adiposity, with stronger effects observed in females. Lower KLF14 expression has been associated with detrimental metabolic phenotypes; however, the therapeutic effect of KLF14 germline overexpression remains unexplored. Here, we generated an adipocyte-specific Klf14 overexpression mouse model to investigate its role in metabolic regulation. Transgenic overexpression conferred sex-dependent metabolic benefits, including reduced weight gain, improved body composition, and enhanced acute insulin sensitivity, predominantly in female mice. These effects were accompanied by increased expression of genes involved in lipid uptake and thermogenic browning of white adipose tissue. Our findings demonstrate that KLF14 overexpression confers protective metabolic effects in a sex-specific manner and support the potential of KLF14-targeted strategies for treating metabolic syndrome.
代谢综合征是一组包括腹型肥胖在内的心血管代谢危险因素，会使个体易患2型糖尿病和心血管疾病。一个经常被重复验证的代谢综合征基因关联信号位于KLF14附近，与中心性肥胖有关，在女性中观察到的影响更强。较低的KLF14表达与有害的代谢表型有关；然而，KLF14种系过表达的治疗效果仍未得到探索。在这里，我们生成了一种脂肪细胞特异性Klf14过表达小鼠模型，以研究其在代谢调节中的作用。转基因过表达赋予了性别依赖性的代谢益处，包括体重增加减少、身体组成改善和急性胰岛素敏感性增强，主要发生在雌性小鼠中。这些作用伴随着参与脂质摄取和白色脂肪组织产热褐变的基因表达增加。我们的研究结果表明，KLF14过表达以性别特异性方式赋予保护性代谢作用，并支持以KLF14为靶点的策略治疗代谢综合征的潜力。
