Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria. Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Maintenance of energetic homeostasis during periods of limited supply requires metabolic adaptation. Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria (MMAuria), present unique challenges to this homeostasis by disrupting energetic pathways. To better understand the systemic and cellular responses to long-term energy shortage, we investigated a hemizygous mouse model of MMAuria that has a knock-in (ki) missense allele combined with a knock-out (ko) allele (Mmut-ko/ki) and shows typical clinical features including reduced growth. We found that Mmut-ko/ki (mutant) mice, compared to their Mmut-ki/wt (control) littermates, have reduced body mass along with a relative reduction in lean mass but increase in fat mass. White adipose tissue appears histologically normal, but brown adipose tissue show a process of whitening, in line with their lower body surface temperature and lesser ability to cope with cold challenge. Ad libitum fed mice show constitutive hypometabolism: they have reduced food intake, reduced energy expenditure, and reduced plasma glucose, but elevated lactate and fibroblast growth factor 21 (Fgf21). Together, these changes culminate in a loss of metabolic flexibility in mutant mice. This is manifested in lesser ability to regulate energy sources when switching from the fed to fasted state, and in a delayed glucose clearance in response to exogenous glucose and insulin. Liver investigations find multi-metabolite accumulation and suggest upregulation of peroxisome proliferator-activated receptor (Ppar)- and Fgf21-controlled metabolic pathways, including beta-oxidation, and downregulation of oxidative phosphorylation, as molecular consequences. Altogether, this study identifies a multi-faceted metabolic response to chronic energy shortage in MMAuria and suggests hypometabolism combined with dysregulated adaptive capability to be underlying features. Overall design: We performed gene expression microarray analysis of liver from mice hemizygous for Mmut and control animals

在营养供给受限时期维持能量稳态，需要机体产生代谢适应性调整。包括孤立性甲基丙二酸血症（methylmalonic aciduria, MMAuria）在内的线粒体代谢遗传性疾病，会通过破坏能量通路，给该稳态维持带来独特挑战。为深入阐明长期能量匮乏下的系统性与细胞应答机制，我们构建并研究了一种MMAuria半合子小鼠模型：该模型携带敲入（knock-in, ki）错义等位基因与敲除（knock-out, ko）等位基因（命名为Mmut-ko/ki），并表现出包括生长迟缓在内的典型临床特征。研究发现，与Mmut-ki/wt（野生型对照）同窝小鼠相比，Mmut-ko/ki（突变型）小鼠体重显著降低，瘦体重相对减少，而脂肪体重却有所增加。白色脂肪组织在组织学上未见明显异常，但棕色脂肪组织却呈现白化进程，这与突变型小鼠较低的体表温度以及较弱的冷应激耐受能力相符。自由采食状态下的突变型小鼠表现出持续性代谢减退：其进食量、能量消耗与血浆葡萄糖水平均有所降低，但乳酸与成纤维细胞生长因子21（fibroblast growth factor 21, Fgf21）水平却显著升高。上述变化最终导致突变型小鼠的代谢灵活性丧失，具体表现为：从进食状态切换至禁食状态时，其能量来源调控能力减弱；对外源性葡萄糖与胰岛素的葡萄糖清除反应也出现延迟。对肝脏的分子分析显示，突变型小鼠体内存在多种代谢物蓄积，且代谢通路呈现双向异常：过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor, Ppar）与Fgf21调控的代谢通路（包括β-氧化）出现上调，而氧化磷酸化通路则被下调。综上，本研究阐明了MMAuria模型小鼠在慢性能量匮乏下的多维度代谢应答，并提出代谢减退与适应性调控能力失调是该疾病的核心病理特征。实验整体设计：我们对Mmut半合子小鼠与对照小鼠的肝脏样本开展了基因表达微阵列分析。