Early life energy expenditure deficits drive obesity in a mouse model of Alstrom syndrome

Abstract

Alstrom syndrome (AS) is a rare multi-system disorder for which early-onset childhood obesity is a cardinal feature. Like humans with AS, animal models with Alms1 loss-of-function mutations develop obesity, supporting the notion that ALMS1/Alms1 is required for the regulatory control of energy balance across species. This study aimed to determine which component(s) of energy balance are reliant on Alms1. Here, we performed comprehensive energy balance phenotyping Alms1tvrm102 mice at both eight- and eighteen-weeks-of-age. We found that adiposity gains occurred early and rapidly in Alms1tvrm102 male mice but much later in females. Rapid increases in body fat in males was due to a marked reduction in energy expenditure (EE) during early life and not due to any genotype-specific increases in energy intake under chow conditions. Energy intake did increase in a genotype-specific manner when mice were provided a high-fat-diet, exacerbating the effects of reduced EE on obesity progression. The EE deficit observed in male Alms1tvrm102 mice did not persist as mice aged, suggesting loss of Alms1 either causes a developmental delay in the mechanisms controlling early life EE, or that activation of compensatory mechanisms occurs after obesity is established. Future studies will determine how ALMS1/Alms1 modulates EE and how sex moderates this process.