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. We performed gene expression microarray analysis of liver from mice hemizygous for Mmut and control animals