RT Journal Article SR Electronic T1 Early life energy expenditure deficits drive obesity in a mouse model of Alström syndrome JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.12.03.471145 DO 10.1101/2021.12.03.471145 A1 Erin J Stephenson A1 Clint E Kinney A1 Amanda S Statyton A1 Joan C Han YR 2021 UL http://biorxiv.org/content/early/2021/12/04/2021.12.03.471145.abstract AB Alström syndrome is an extremely rare multi-system disorder for which early-onset childhood obesity is one of the cardinal features. Similar to humans with Alström syndrome, animal models with Alms1 loss of function mutations develop obesity, strongly supporting the notion that ALMS1/Alms1 is required for the regulatory control of energy balance across species. To determine which component(s) of energy balance are reliant on functional Alms1, we performed comprehensive energy balance phenotyping of the tvrm102 mouse model of Alström syndrome. We found that that adiposity gains occurred early and rapidly in male mice but much later in females. Rapid increases in body fat in males were, at least in part, due to a marked reduction in energy expenditure during early life and not due to any genotype-specific influence over energy intake. Energy intake did increase in a genotype-specific manner when mice were provided a palatable, high-energy diet, although this was not necessary for the initial establishment of obesity. Interestingly, the energy expenditure deficit observed in male Alms1-/-mice did not persist as mice age, suggesting that loss of Alms1 either causes a developmental delay in the mechanisms controlling early life energy expenditure, or that there is activation of compensatory mechanisms after obesity is established. Future studies will tease out how ALMS1/Alms1 modulates energy expenditure in early life and how sex moderates this process.Competing Interest StatementJ.C.H. is a site-PI for a multicenter clinical trial sponsored by Rhythm Pharmaceuticals. The remaining authors have no conflict of interest to declare.