From the Burke Medical Research Institute, White Plains, New York 10605 and.
From the Burke Medical Research Institute, White Plains, New York 10605 and
J Biol Chem. 2018 Aug 24;293(34):13338-13348. doi: 10.1074/jbc.RA118.002405. Epub 2018 Jun 18.
Obesity-induced metabolic dysfunctions increase the risk for vascular diseases, including type II diabetes and stroke. Managing obesity is of interest to address the worldwide health problem; however, the role of genetic variability in human obesity development and specific targets for obesity-related metabolic disease have not been thoroughly studied. A SNP in the brain-derived neurotropic factor () gene that results in the substitution of a valine with a methionine at codon 66 () occurs with a high frequency in humans. This study addressed the effect of genetic variability in developing obesity and the efficacy of the inhibition of cluster of differentiation 36 (CD36), a multifunctional receptor implicated in obesity and insulin resistance, in WT mice and mice with the variant. CD36 inhibition by salvionolic acid B (SAB) in diet-induced obese WT mice reduced visceral fat accumulation and improved insulin resistance. The benefit of SAB was abrogated in CD36 knockout mice, showing the specificity of SAB. In addition, mice with the variant in both alleles (BDNF) fed a high-fat diet exhibited extreme obesity with increased CD36 gene and protein levels in macrophages. Chronic SAB treatment in BDNF mice significantly decreased visceral fat accumulation and improved insulin resistance. Notably, the effect of SAB was greater in the extremely obese BDNF mice compared with the WT mice. The study demonstrated a link between and elevated CD36 expression and suggested that CD36 inhibition may be a potential strategy to improve metabolic dysfunctions and to normalize risk factors for vascular diseases in the obese population.
肥胖引起的代谢功能紊乱增加了患血管疾病的风险，包括 2 型糖尿病和中风。控制肥胖是解决全球健康问题的关键；然而，遗传变异在人类肥胖发展中的作用以及肥胖相关代谢疾病的具体靶点尚未得到充分研究。脑源性神经营养因子（BDNF）基因中的一个 SNP 导致密码子 66 处的缬氨酸被蛋氨酸取代（Val66Met），这种 SNP 在人类中发生的频率很高。本研究探讨了遗传变异在肥胖发展中的作用，以及抑制分化簇 36（CD36）对 WT 小鼠和携带 变异体小鼠的疗效。在饮食诱导肥胖的 WT 小鼠中， salvionolic 酸 B（SAB）抑制 CD36 减少内脏脂肪堆积并改善胰岛素抵抗。在 CD36 敲除小鼠中，SAB 的益处被消除，表明 SAB 的特异性。此外，两种等位基因（BDNF）均携带 变异体的高脂肪饮食喂养的小鼠表现出极度肥胖，巨噬细胞中 CD36 基因和蛋白水平升高。慢性 SAB 治疗 BDNF 小鼠可显著减少内脏脂肪堆积并改善胰岛素抵抗。值得注意的是，与 WT 小鼠相比，SAB 在极度肥胖的 BDNF 小鼠中的效果更大。该研究表明 与 CD36 表达升高之间存在关联，并表明 CD36 抑制可能是改善肥胖人群代谢功能紊乱和使血管疾病风险因素正常化的潜在策略。
