School of Health Sciences, The University of Tasmania, Launceston, Tasmania, Australia.
Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Diabetes Obes Metab. 2024 May;26(5):1731-1745. doi: 10.1111/dom.15484. Epub 2024 Feb 13.
Acyl-coenzyme A dehydrogenase family member 10 (ACAD10) is a mitochondrial protein purported to be involved in the fatty acid oxidation pathway. Metformin is the most prescribed therapy for type 2 diabetes; however, its precise mechanisms of action(s) are still being uncovered. Upregulation of ACAD10 is a requirement for metformin's ability to inhibit growth in cancer cells and extend lifespan in Caenorhabditis elegans. However, it is unknown whether ACAD10 plays a role in metformin's metabolic actions.
We assessed the role for ACAD10 on whole-body metabolism and metformin action by generating ACAD10KO mice on a C57BL/6J background via CRISPR-Cas9 technology. In-depth metabolic phenotyping was conducted in both sexes on a normal chow and high fat-high sucrose diet.
Compared with wildtype mice, we detected no difference in body composition, energy expenditure or glucose tolerance in male or female ACAD10KO mice, on a chow diet or high-fat, high-sucrose diet (p ≥ .05). Hepatic mitochondrial function and insulin signalling was not different between genotypes under basal or insulin-stimulated conditions (p ≥ .05). Glucose excursions following acute administration of metformin before a glucose tolerance test were not different between genotypes nor was body composition or energy expenditure altered after 4 weeks of daily metformin treatment (p ≥ .05). Despite the lack of a metabolic phenotype, liver lipidomic analysis suggests ACAD10 depletion influences the abundance of specific ceramide species containing very long chain fatty acids, while metformin treatment altered clusters of cholesterol ester, plasmalogen, phosphatidylcholine and ceramide species.
Loss of ACAD10 does not alter whole-body metabolism or impact the acute or chronic metabolic actions of metformin in this model.
酰基辅酶 A 脱氢酶家族成员 10（ACAD10）是一种线粒体蛋白，据称参与脂肪酸氧化途径。二甲双胍是治疗 2 型糖尿病最常用的药物；然而，其确切的作用机制仍在探索中。ACAD10 的上调是二甲双胍抑制癌细胞生长和延长秀丽隐杆线虫寿命的能力所必需的。然而，目前尚不清楚 ACAD10 是否在二甲双胍的代谢作用中发挥作用。
我们通过 CRISPR-Cas9 技术在 C57BL/6J 背景下生成 ACAD10KO 小鼠，以评估 ACAD10 在全身代谢和二甲双胍作用中的作用。在正常饲料和高脂肪高蔗糖饮食中对两性进行了深入的代谢表型分析。
与野生型小鼠相比，在雄性或雌性 ACAD10KO 小鼠中，无论在正常饮食还是高脂肪高蔗糖饮食下，我们都没有检测到体成分、能量消耗或葡萄糖耐量的差异（p≥.05）。在基础或胰岛素刺激条件下，基因型之间的肝线粒体功能和胰岛素信号没有差异（p≥.05）。在葡萄糖耐量试验前给予二甲双胍急性给药后，葡萄糖波动没有基因型差异，4 周的每日二甲双胍治疗后体成分或能量消耗也没有改变（p≥.05）。尽管没有代谢表型，但肝脏脂质组学分析表明，ACAD10 缺失会影响含有超长链脂肪酸的特定神经酰胺的丰度，而二甲双胍治疗会改变胆固醇酯、质体、磷脂酰胆碱和神经酰胺的簇。
在该模型中，ACAD10 的缺失不会改变全身代谢或影响二甲双胍的急性或慢性代谢作用。
