Department of Endocrinology and Metabolism, Molecular Endocrinology & Stem Cell Research Unit (KMEB) Odense University Hospital, University of Southern Denmark, Odense, Denmark.
Biomechanics Section, Department of Mechanical Engineering, KU Leuven, Heverlee, Belgium.
Aging Cell. 2022 Dec;21(12):e13726. doi: 10.1111/acel.13726. Epub 2022 Oct 10.
Several epidemiological studies have suggested that obesity complicated with insulin resistance and type 2 diabetes exerts deleterious effects on the skeleton. While obesity coexists with estrogen deficiency in postmenopausal women, their combined effects on the skeleton are poorly studied. Thus, we investigated the impact of high-fat diet (HFD) on bone and metabolism of ovariectomized (OVX) female mice (C57BL/6J). OVX or sham operated mice were fed either HFD (60%fat) or normal diet (10%fat) for 12 weeks. HFD-OVX group exhibited pronounced increase in body weight (~86% in HFD and ~122% in HFD-OVX, p < 0.0005) and impaired glucose tolerance. Bone microCT-scanning revealed a pronounced decrease in trabecular bone volume/total volume (BV/TV) (-15.6 ± 0.48% in HFD and -37.5 ± 0.235% in HFD-OVX, p < 0.005) and expansion of bone marrow adipose tissue (BMAT; +60.7 ± 9.9% in HFD vs. +79.5 ± 5.86% in HFD-OVX, p < 0.005). Mechanistically, HFD-OVX treatment led to upregulation of genes markers of senescence, bone resorption, adipogenesis, inflammation, downregulation of gene markers of bone formation and bone development. Similarly, HFD-OVX treatment resulted in significant changes in bone tissue levels of purine/pyrimidine and Glutamate metabolisms, known to play a regulatory role in bone metabolism. Obesity and estrogen deficiency exert combined deleterious effects on bone resulting in accelerated cellular senescence, expansion of BMAT and impaired bone formation leading to decreased bone mass. Our results suggest that obesity may increase bone fragility in postmenopausal women.
几项流行病学研究表明，肥胖伴有胰岛素抵抗和 2 型糖尿病会对骨骼产生有害影响。虽然绝经后妇女同时存在肥胖和雌激素缺乏，但它们对骨骼的综合影响研究甚少。因此，我们研究了高脂肪饮食（HFD）对去卵巢（OVX）雌性小鼠（C57BL/6J）骨骼和代谢的影响。OVX 或假手术小鼠分别用 HFD（60%脂肪）或正常饮食（10%脂肪）喂养 12 周。HFD-OVX 组体重明显增加（HFD 组增加约 86%，HFD-OVX 组增加约 122%，p<0.0005），葡萄糖耐量受损。骨微 CT 扫描显示，骨小梁体积/总体积（BV/TV）明显减少（HFD 组减少 15.6±0.48%，HFD-OVX 组减少 37.5±0.235%，p<0.005），骨髓脂肪组织（BMAT）扩张（HFD 组增加 60.7±9.9%，HFD-OVX 组增加 79.5±5.86%，p<0.005）。从机制上讲，HFD-OVX 治疗导致衰老、骨吸收、脂肪生成、炎症的基因标志物上调，骨形成和骨发育的基因标志物下调。同样，HFD-OVX 治疗导致嘌呤/嘧啶和谷氨酸代谢的骨组织水平发生显著变化，已知这些代谢物在骨代谢中发挥调节作用。肥胖和雌激素缺乏对骨骼产生联合的有害影响，导致细胞衰老加速、BMAT 扩张和骨形成受损，导致骨量减少。我们的结果表明，肥胖可能会增加绝经后妇女的骨脆性。
